2011
Benha University
Faculty of Science
Chemistry Department
Synthesis and Reactions of Some Heterocyclic
compounds of Expected Biological Activity
A thesis
Submitted in partial fulfillment
of the requirements of master degree in chemistry
Submitted by
Esraa Azmy Abd El-Wahab (Bachelor of Science in Chemistry)
Submitted To Chemistry Department - Faculty of Science -BenhaUniversity
Supervised by
Prof. Dr.
Ashraf Abd El-Hamid Wasfy Professor of Organic Chemistry
Chemistry Department
Faculty of Science
Benha University
Prof. Dr.
Mohamed Abo El-Ela Radwan Professor of Applied Chemistry
Faculty of Engineering
Shoubra
Benha University
Dr.
Ali Abd El-Maboud Ali Ass. Professor of Organic Chemistry
Chemistry Department
Faculty of Science
Benha University
Dr.
Manal Mahmoud El-Hefnawy Lecture of Organic Chemistry
Faculty of Engineering
Shoubra
Benha University
﴿ فضم للاه تعهى وكا ك يا نى تك ت وعهه عهيك انكتاب وانحك زل للاه وأ
ا ﴾عهيك عظي
صذق للا انعظيى
(١١١)سىرة انساء آيه
DEDICATION
To
My Husband
Benha University
Faculty of Science
Chemistry Department
Title: Synthesis and Reactions of Some Heterocyclic compounds of
Expected Biological Activity
Student name: Esraa Azmy Abd El-Wahab
Supervisors:
Thesis approved Thesis advisors
Prof. Dr. Ashraf Abdel-Hamid Wasfy
Prof. Dr. Mohamed Abo El-Ela Radwan
Dr. Ali Abd El-Maboud Ali
Dr. Manal Mahmoud El-Hefnawy
Prof. Dr. Shafei Galal Donia
Head of Chemistry Department
PRE-MASTER COURSES
Beside the work carried out in this thesis the candidate has attended Post-
graduate courses in organic chemistry
Covering the following topics:
1. Physical organic chemistry
2. Heterocyclic chemistry
3. Analytical organic chemistry
4. Organic spectroscopy
5. Applied organic chemistry
6. Selected courses
7. English language
Prof. Dr. Shafei Galal Donia
Head of Chemistry Department
ABSTRACT
N-(2-(4-chlorophenyl)-1-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)vinyl)-2-(1,3-
dioxoisoindolin-2-yl)acetamide 2 was synthesized by treatment of anthranilic
acid with (Z)-2-((4-(4-chlorobenzylidene)-5-oxo-4,5-dihydrooxazol-2-
yl)methyl)isoindoline-1,3-dione 1 in boiling butanol. The reactions of 2 with
nitrogen and carbon nucleophiles and with carbon electrophiles was
investigated.
ACKNOWLEDGMENTS
First and foremost thanks to ALLAH, the most compassionate and the most
merciful.
I would like also to thanks Prof. Dr. Ashraf Abd El-Hamid Wasfy, Professor
of Organic Chemistry, Faculty of Science, Benha University for his supervision,
useful guidance, encouragement and facilities he offered me throughout the
progress of this work.
I would like also to express my sincere thanks and deepest gratitude appreciation
to Dr. Ali Abd El-Maboud Ali, Ass.Professor of Organic Chemistry, Faculty of
Science, Benha Universityfor his guiding the work during experimental
measurements, supervision and continuous help.
I am extremely grateful to Prof.Dr. Mohamed Abo El-Ela Radwan, Professor
of Applied Chemistry, Faculty of Engineering, Benha University for his kind
supervision.
Deep thanks to Dr.Manal Mahmoud El-Hefnawy, Lecture of Organic
Chemistry, Faculty of Engineering, Benha University for her supervision and
encouragement.
I would like to thank my parents, my brothers for their endless support,
encouragement and love.
I am so indebted to my husband he has been, always, my pillar and my guiding
light. Without the love and support of my husband, I would not have finished
this work. Thank you, my husband, for everything.
Finally, my thanks also extend to all the staff members and my colleagues in
faculty of Engineering and Faculty of Science, Benha University for their
cooperation and encouragement during this work.
TABLE OF CONTENTS
1. SUMMARY .................................................................................................. i
2. AIM OF THE WORK ................................................................................. iii
3. INTRODUCTION ....................................................................................... 1
1. Importance of 4H-3,1-benzoxazin-4-ones ....................................................................................... 1
1.1 Pharmaceutical applications of 4H-3,1-benzoxazin-4-ones ...................................................... 1
1.2 Industrial applications ............................................................................................................... 3
2. Synthesis of 4H-3,1-benzoxazin-4-ones .......................................................................................... 3
2.1 From anthranilic acids ............................................................................................................... 3
2.1.1 Via the action of acid chlorides on anthranilic acid ........................................................... 3
2.1.2 Via the action of acid anhydrides on anthranilic acid ....................................................... 8
2.1.3 Via reaction of anthranilic acid with aromatic carboxylic acid ........................................ 11
2.1.4 Reaction of substituted anthranilic acid with Boc-protected amino acids ...................... 12
2.1.5 Reaction of substituted anthranilic acid with 2,2-dihydro fluoroalkanoic acid ............... 13
2.1.6 Synthesis of Bis(411)-3,1-benzoxazin-4-one derivatives :- .............................................. 13
2.1.7 From interaction of anthranilic acid with heterocyclic compounds ................................ 14
2.1.7.1 From 4-arylidene-2-aryl-oxazoIin-5-one ................................................................... 14
2.1.7.2 From iminodithiazole ................................................................................................ 14
2.1.7.3 From (4H)-3,2-benzoxazin-4-one .............................................................................. 15
2.1.7.4 From 3- methyl-2-(ethoxycarbonylmethoxy) quinoxaline ........................................ 15
2.1.7.5 From 2-ethoxycarbonyl-4(3H)-quinazolin-4-one ...................................................... 15
2.1.7.6 From substituted coumarin ....................................................................................... 16
2.1.7.7 From hetero-ring opening of furanone derivatives .................................................. 17
2.1.7.8 From hetero-ring opening of 1,3-dioxin-4-one derivatives ...................................... 17
2.2 From N-acylanthranilic acid..................................................................................................... 17
2.2.1 Acetic anhydride as cyclizing agent .................................................................................. 17
2.2.2 Thionyl chloride as cyclizing agent ................................................................................... 18
2.2.3 Vilsmeier reagents as cyclizing agent ............................................................................... 18
2.2.4 Cyanuric chloride as cyclizing agent ................................................................................. 19
2.2.5 Dicyclohexylcarbodiimide as cyclizing agent .................................................................... 19
2.3 From 2-methyl-4H-3,1-benzoxazin-4-one ............................................................................... 20
2.4 From isatoic anhydrides .......................................................................................................... 21
2.4.1 Reaction of isatoic anhydride with acid anhyd rides ..................................................... 21
2.4.2 Reaction of isatoic anhydride with acid chlorides ......................................................... 22
2.4.3 Reaction of isatoic anhydride with phosphoryl- stabilized anions ............................... 23
2.5 Oxidation of indoles ............................................................................................................... 23
2.6 Miscellaneous .......................................................................................................................... 24
2.6.1 From β-(Triphenylphosphoranylidene)amino esters ...................................................... 24
2.6.2 From iminophosphorane .................................................................................................. 25
2.6.3 From N-benzenesulphonylanthranilic acid ...................................................................... 25
2.6.4 From thioamide derivatives ............................................................................................. 25
2.6.5 From electrochemical trichloroacetylanilides .................................................................. 25
2.6.6 CO2 Incorporation reaction using arynes ......................................................................... 26
2.6.7 From 2-(1H-1,2,3-benzotrizol-1-yl)phenylethanone ........................................................ 26
2.6.8 From heating of acetylanthranilic acid by microwave .................................................. 27
2.6.9 Thermolysis of 2-(3-benzoylthioureido)-4,5-dimethoxy benzoic acid ............................ 28
2.6.10 Thermally induced cyclization of ketenimines ............................................................... 28
2.6.11 From o-iodoaniline ......................................................................................................... 28
3. Reactions of 4H-3,1-benzoxazin-4-ones ........................................................................................ 30
3.1 Reactions with Hydrogen nucleophiles ................................................................................... 30
3.2 Reactions with Oxygen nucleophiles ....................................................................................... 30
3.3 Reactions with nitrogen nucleophiles ..................................................................................... 31
3.3.1 Ammonlysis ...................................................................................................................... 32
3.3.2 Hydrazinolysis ................................................................................................................... 33
3.3.2.1 Reactions with hydrazine hydrate ............................................................................. 33
3.3.2.2 Reaction with hvdrazine hydrate in presence of carbondisulphide ......................... 37
3.3.2.3 Reaction with subsitituted hydrazines ...................................................................... 38
3.3.2.4 Reactions with hydroxylamine hydrochloride .......................................................... 40
3.3.2.5 Reactions with thiosemicarbazide and aminoguanidines ......................................... 40
3.3.3 Aminolysis ........................................................................................................................ 41
3.3.3.1 Reactions with primary nonaromatic amines ........................................................... 41
3.3.3.2 Reactions with secondary amines ............................................................................. 43
3.3.3.3 Reactions with alkylamines ....................................................................................... 44
3.3.3.3.1 Reactions with benzylamine ............................................ 44
3.3.3.3.2 Reactions with phenylethylamine .................................... 45
3.3.3.4 Reactions with anilines .............................................................................................. 48
3.3.3.4.1 Reactions with p-bromoanilines ...................................... 49
3.3.3.4.2 Reactions with p-aminodiphenylamine ........................... 49
3.3.3.4.3 Reactions with o-toluidine ............................................... 49
3.3.3.4.4 Reactions with 2-substituted and/or 2,6-disubstituted
anilines ............................................................................................ 50
3.3.3.4.5 Reactions with anilines containing reactive function
groups .............................................................................................. 51
3.3.3.4.5.1 Reaction with 2-cyanoanilines .................................................................... 51
3.3.3.4.5.2 Reactions with p-aminoacetophenone ....................................................... 52
3.3.3.4.5.3 Reactions with 4-hydroxyanilines ............................................................... 53
3.3.3.4.5.4 Reactions with sulphanilamide ................................................................... 53
3.3.3.5 Reactions with amino heterocyclic compounds ....................................................... 54
3.3.3.6 Reactions with diamines ........................................................................................... 56
3.3.3.6.1 Reactions with o-phenylenediamine ................................ 56
3.3.3.6.2 Reactions with ethylenediamine ...................................... 58
3.3.3.6.3 Reactions with p-phenylenediamine ................................ 58
3.3.3.7 Reactions with aminoacids ........................................................................................ 59
3.3.3.8 Reactions with aminoalcohols................................................................................... 60
3.3.3.9 Reactions with Schiff’s bases .................................................................................... 61
3.3.3.10 Reactions with azines .............................................................................................. 61
3.3.3.11 Reactions with sodium azide ................................................................................... 62
3.3.4 Reactions with carbon nucleophiles ................................................................................ 62
3.3.4.1 Reactions with Grignard reagents ............................................................................. 62
3.3.4.2 Friedel-Crafts reactions ............................................................................................. 67
3.3.4.3 Reactions with active methylene containing compounds ........................................ 68
4. DISCUSSION ............................................................................................ 72
1. Synthesis and reactions of N-(2-(4-chlorophenyl)-1-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)vinyl)-2-
(1,3-dioxoisoindolin-2-yl)acetamide ................................................................................................. 72
1.1 The structure of compound (2) was established from the following:..................................... 72
1.2 Chemical proven of compound (2) .......................................................................................... 75
1.2.1 Reaction with amines ....................................................................................................... 75
1.2.1 Hydrazinolysis ................................................................................................................... 79
2. Base catalyzed of 3,1-(4H)-benzoxazinone (2) with active methylene compounds ..................... 80
3. Action of sodium azide .................................................................................................................. 80
4. Friedel-Crafts reaction ................................................................................................................... 81
5. Reaction with 2-amino methyl benzimidazole .............................................................................. 83
6. Diels-Alder reaction ....................................................................................................................... 83
7. Synthesis of quinazolinyl urea ....................................................................................................... 85
8. Synthesis of triazino quinazolinone derivative ............................................................................. 85
9. Ammonolysis ................................................................................................................................. 88
9.1 Chemical proven of compound (14) ........................................................................................ 89
9.1.1 Acylation of (14) ............................................................................................................... 89
9.1.2 Acetylation of quinazol-4-one (14) ................................................................................... 90
9.1.3 Action of phosphorus pentachloride - phosphorus oxychloride on quinazol-4-one (14) 91
10. Mannish reaction ........................................................................................................................ 91
11. Synthesis of ethyl 2-(2-(2-(4-chlorophenyl)-1-(2-(1,3-dioxoisoindolin-2-
yl)acetamido)vinyl)quinazolin-4-yloxy)acetate ................................................................................. 93
11.1 Chemical proven of compound (19) ...................................................................................... 94
12. Action of phenyl isocyanate on quinazolinone (20) .................................................................... 94
13. Action of p-chlorobenzaldhyde on quinazolinone (20) ............................................................. 95
14. Base catalysed reaction with hydroxylamine hydrochloride ...................................................... 95
14.1 Chemical proven of compound (23) ...................................................................................... 96
14.1.1 Acetylation of 3-N-hydroxy-4-quinazolone .................................................................... 96
14.1.2 Reaction with ethyl chloroacetate ................................................................................. 97
14.1.2.1 Chemical proven of compound (25) ........................................................................ 97
15. Action of phenyl isocyanate on quinazolinone (26) .................................................................... 98
16. Action of p-chlorobenzaldhyde on quinazolinone (26) ............................................................... 98
5. BILOGICAL ACTIVITY ........................................................................ 100
6. BIOLOGICAL ACTIVITY ..................................................................... 105
7. EXPERMINTAL ..................................................................................... 110
1. Synthesis and reactions of N-(2-(4-chlorophenyl)-1-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)vinyl)-2-
(1,3-dioxoisoindolin-2-yl)acetamide (2) .......................................................................................... 110
2. Action of primary amines on (2): formation of (3a-h) .................................................................. 110
3. Action of hydrazines on (2): Formation of (4a,b) .......................................................................... 110
4. Action of active methylene on benzoxazinone (2): Formation of 1,4-quinolinone (5) ............... 110
5. Action of sodium azide on benzoxazinone (2): Formation of tetrazole (6) ................................ 111
6. Action of aromatic substrates on benzoxazinone (2) in presence of anhydrous AlCl3: Formation
of o-aroylanilides (7a,b) .................................................................................................................... 111
7. 2-Amino methyl benzimidazole (8) ............................................................................................. 111
8. Action of (8) on benzoxazinone (2): Formation of 2-substdituted- 3-methyl-[2'-benzimidazolyl]-
( 4H)- 3,1-quinazolin-4-one (9) ........................................................................................................ 111
9. Diels-Alder reaction on (2): ......................................................................................................... 111
10. Synthesis of quinazolinylurea (11) ............................................................................................ 111
11. Cyclization of quinazolinylurea(12) ........................................................................................... 112
12. Action of thiosemicarbazide on benzoxazone (2) ..................................................................... 112
13. Action of ammonium acetate or formamide on (2):Formation of quinazolone (14) ............... 112
14. Acylation of (14): Formation of (15) .......................................................................................... 112
15. Action of acetic anhydride on (14): Formation of 3N-acetyl quinazolone (16) ........................ 112
16. Action of phosphorus pentachloride - phosphorus oxychloride on quinazol-4-one (14) ......... 112
17. Mannish reaction on quinazolone (14): Formation of Mannish bases (18) .............................. 112
18. Action of ethyl chloroacetate on quinazolinone (14) ............................................................... 113
19. Action of hydrazine hydrate on quinazolinone (19) .................................................................. 113
20. Action of phenyl isocyanate on quinazolinone (20) .................................................................. 113
21. Action of aldehyde on quinazolinone (20) ................................................................................ 113
22. Action of hydroxylamine hydrochloride on benzoxazone (2) Formation of 3-hydroxy-4-
quinazolone (23) ............................................................................................................................. 113
23. Action of acetic anhydride 3-hydroxy quinazolone (23) Formation of (24) .............................. 113
24. Action of ethyl chloroacetate on 3-hydroxy-4-quinazolone (23) .............................................. 113
25. Action of hydrazine hydrate on quinazolinone (25) .................................................................. 114
26. Action of phenyl isocyanate on quinazolinone (26) ................................................................. 114
27. Action of aldehyde on quinazolinone (26) ................................................................................ 114
8. REFERENCES......................................................................................... 123
i
SUMMARY
This study presents the synthesis of the N-(2-(4-chlorophenyl)-1-(4-oxo-4H-
benzo[d][1,3]oxazin-2-yl)vinyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide (2). It
was synthesized by treatment of anthranilic acid with (Z)-2-((4-(4-
chlorobenzylidene)-5-oxo-4,5-dihydrooxazol-2-yl)methyl)isoindoline-1,3-dione
(1).Amminolysis of (2) gave 2-(substituted)-carbamoyl phenyl acetanilides(3a-h).
The benzoxazinone (2) underwent ring fission of the hetero cyclic ring when
heated with hydrazine hydrate and gave the amide derivative (4a). On the other
hand, reaction of (2) with phenyl hydrazine, yielded quinazolinone derivative
(4b).
While treatment of (2) with ethyl acetoacetate gave carbethoxy 3,4-dihydro-1,4-
quinolinone derivative (5).
Benzoxazinone (2) reacted with sodium azide and yielded tetrazole (6). While
treatment of (2) with anhydrous AlCl3 in hydrocarbons under the Fridel-Crafts
condition reaction gave o-substituted phenyl aryl ketones (7a,b).
On the other hand, Mannich reaction of (2) gave Mannich base (9). While
treatment of (2) with dimethyl maleate in dry xylene gave the corresponding
Diels-Alder adducts (10).
Otherwise, benzoxazinone (2) was allowed to react with semicarbazide
hydrochloride in boiling pyridine which afforded quinazolinyl urea derivative
(11). On fusion of the above compound at its melting point it was cyclized to
produce triazole quinazoline derivative (12).
Moreover, benzoxazinone (2) was treated with thiosemicarbazide in boiling
pyridine and afforded (13).
While ammonolysis of (2) gave the corresponding 2-substituted-4(3H)-
quinazol-4-one derivative (14). The lactam-lactim tautomerism of (14) was
further demonstrated chemically by studies the effect of alkylating agent, acetic
anhydride, a mixture of phosphorus pentachloride and phosphorus oxychloride
and Mannichreaction to give 4-(substiuted)-2-(substiuted)-quinazolin-4-
ones(15), 3N-acetyl-2-(substituted)-quinazolin-4-one (16), 2-(substituted)vinyl-
4-chloroquinazolin-4-one (17) and the Mannich base 3N-(substituted)-
quinazolin-4-one (18) respectively.
Quinazolinone (14) reacts with ethyl chloroacetate in dry acetone and in the
presence of dry potassium carbonate to give compound (19) which was further
ii
demonstrated chemically byhydrazinolysis of the ester by hydrazine hydrate to
yield the hydrazide derivative (20).
Furthermore, the hydrazide derivative (20) wasreacted with phenyl isocyanate in
dioxane and p-chlorobenzaldhyde in absolute ethanol and 1ml pipridine to give
(21) and (22) respectively.
Benzoxazinone (2)reacted with hydroxylamine hydrochloride in the presence of
sodium acetate in boiling ethanol to give N-(2-(4-chlorophenyl)-1-(3-hydroxy-4-
oxo-3,4-dihydroquinazolin-2-yl)vinyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide
(22).
On the other hand, 3-N-hydroxy-4-quinazolone derivative (23) used as a key
starting material for synthesis of some interesting heterocyclic compounds and it
was further demonstrated chemically by studies the effect of acetic anhydride
and ethyl chloroacetateto give2-(2-(4-chlorophenyl)-1-(2-(1,3-dioxoisoindolin-
2-yl)acetamido)vinyl)-4-oxoquinazolin-3(4H)-yl acetate (24) and ethyl 2-(2-(2-
(4-chlorophenyl)-1-(2-(1,3-dioxoisoindolin-2-yl)acetamido)vinyl)-4-
oxoquinazolin-3(4H)-yloxy)acetate (25) respectively.
The compound (25) was further demonstrated chemically byhydrazinolysis of
the ester by hydrazine hydrate to yield the hydrazide derivative (26).
Moreover, the hydrazide derivative (26) wasreacted with phenyl isocyanate in
dioxane and p-chlorobenzaldhyde in absolute ethanol and 1ml pipridine to give
(27) and (28) respectively.
The structure of all synthesized derivatives compounds is established by: (i)
elemental analysis, (ii) IR, (iii) H1NMR, (iv) Mass spectra.
Biological activities of some synthesized compounds was investigated and the
results are presented.
iii
AIM OF THE WORK
Studying the behavior of 4H-3,1-benzoxazinone derivative towards nitrogen and
carbon nucleophiles and with carbon electrophiles will give a good information
about the extent of the reactivity for 4H-3,1-benzoxazinone derivative
qualitatively .
Moreover, one of the most important features of 4H-3,1-benzoxazinone
derivative in chemistry is its applications as a key starting material for further
transformations. They are useful intermediates for the synthesis of 4(3H)-
quinazolinone derivatives, which can be employed in biological applications.
On the other hand, the behavior of the synthesized organic compounds as
antibacterial was investigated.
INTRODUCTION
Studies on 4H-3,1-Benzoxazin-4-ones
Introduction
1
INTRODUCTION
4H-3,1-benzoxazinones as a class have been known for more than a century.
The phenyl derivative 1a was first synthesized [128] and the methyl analog 1b
seventeen years later [54]. Members of this family have been given the common
name ―acylanthranils‖ presumably from their early synthesis from 2,1-
benzisooxazole (anthranil) and an acylating agent. Compounds possessing this
ring system are found in nature. e.g. Phytoalexins avenalumin [202] and
Dianthalexins 2 [52,147], and some hydroxylated derivatives of this last
compound 3,4 [224].
The present review will covers this important field of fused heterocycles with
nearly all the chemistry (synthesis and reactions) as well as its applications. For
4H-3,1-benzoxazin-4-one derivatives only those with carbon substituents at 2-
position will he mentioned.
1. Importance of 4H-3,1-benzoxazin-4-ones
1.1 Pharmaceutical applications of 4H-3,1-benzoxazin-4-ones
The 4H-3,1-benzoxazin-4-one core is a key structural fragment in a range of
biologically active compounds. Work by medicinal chemists had led to a
number of drugs. Related uses being found for this class of heterocyclic systems.
4H-3,1-benzoxazin-4-ones have attracted considerable attention as inhibitors of
Serine proteases. The interaction of 3,1-benzoxazin-4-ones with serine proteases
involves enzyme acylation due to the nucleophilic attack of the active site of
serine on the lactone carbon, ring cleavage, and subsequent deacylation of the
acylenzyme formed [139,295]. Hays et al. have screened a series of 2-
substituted 4H-3,1-benzoxazin-4-ones as inhibitors of Clr serine protease of the
complement system.
Particularly, 2-aryl-4H-3,1-benzoxazin-4-ones act as Clr Serine protease
inhibitors [133]. Also it was converted into the corresponding 4(3H)-quinazolin-
4-ones interaction with 4-amino-1-phenyl-2,3-dimethyl pyrazolin-5-one
(aminoantipyrine), which act as Non-Steroidal anti-inflammatory agents
[118, 123].
Introduction
2
In a modem fashion, 4H-3,1-benzoxazin-4-ones core linked to heterocycle or
heteroaryl were disclosed as Serine hydrolase inhibitors. They were evaluated in
a human sputum neutrophil elastase assay [274].
Chiral 2-alkylamino 4H-3,1-benzoxazin-4-one derivatives were reported as
inhibitors or potent inactivatores of Standard Serine Proteases of the
Chemotrypsin superfamily [215,289,180].
A series of 2-amino substituted 4H-3,1-benzoxazin-4-one derivatives was
reported as inhibitors for human protease, and some of them demonstrate Anti-
Viral activity in cell culture, with selectivities related to chemotrypsin and
Elastase and stability with respect to hydrolysis in human plasma [8,137,138
,149]. Also a combination of 4H-3,1-benzoxazin-4-one with 2-aminothiadiazole
gives substituted quinazolinone which act as potent Anticonvulsants and
Enzyme inhibitors [275].
5-Methyl-4H-3,1-benzoxazin-4-one derivatives are acomplished as specific
inhibitors of Human. Leukocyte Elastase (HLE), where they showed strong and
highly specific inhibition of Human Sputum Elastase (HSE), which is equivalent
to HLE [302].
Moreover, 2-substituted-4H-3,1-benzoxazin-4-one derivatives showed good
Cytotoxic activity [236], Herbicidal properties and inhibition of Herpes simplex
virus type 1 (HSV-1) protease [145,167]. A series of 4H-3,1-benzoxazin-4-ones
with different aromatic substitution pattern were evaluated as HIV-1 Reverse
transcriptase inhibitors [244].
2-Aryl-substituted 4H-3,1-benzoxazin-4-ones act as novel active substances for
the cardiovscular system. They exhibit relaxing effect on smooth musculature in
particular and markedly increase coronary flow through Langendorff hearts
[304].Moreover, they are used in t treatment of Obesity and also found to be
novel specific Puromycin sensitive aminopeptidase inhibitors [153,307].
Nevertheless, they exhibit biological activates towards anti-elastases. [69].
Clearly, some 2-substituted 4H-3,1-benzoxazin-4-ones have the ability to lower
the levels of cholesterol and triglycerides in plasma, and to raise the proportion
of total cholsterol carried by high-density lipoproteins [124].
The importance of these 4H-3,1-benzoxazin-4-one also resides in that, these
compounds is useful precursors for the preparation of other pharmaceutically
active heterocyclic compounds, mainly quinazoline derivatives [68].
For example, 2-styryl-4-(3R)-quinazolinone bearing 5-,6-, 7-, 8-Cl, 6-Br, 6-F, 6-
NH2, 6-OMe, 6-OH, 6-OEt act as new class of Anti-Miotic Anti-Cancer agents
which inhibited Tubulin polymerization. Extensive structure activity relationship
studies suggest that, the entire quinazolinon structure was required, but activity
was further enhanced by halides or small hydrophobic substituents at position-6
[169].
Introduction
3
While, substituted 2-(1-adamantyl)-4H-3,1-benzoxazin-4-ones and 2-(1-
adamantyl)-3-amino or alkyl-3,4-dihydroquinazolin-4-ones are found to exhibit
a broad spectrum Anti-Tumor activity with full panel (MG-MID) median growth
inhibition (GI50), some of them showed moderate selectivity towards Leukemia
Cell Lines, and some of them possess moderate Anti-HIV-l potency [112].
1.2 Industrial applications
4H-3,1-benzoxazin-4-ones containing at 2-position Ph, m-, p-tolyl, p-
chlorophenyl, m-nitrophenyl, or m-methoxyphenyl are additives comprising
surfactants, carboxypolymers, polysaccharides and/or polyalicylene glycols.
amount of 5-7% of this compounds have good storage stability in detergent
components containing a peroxygen bleach, such as Na perborate tetrahydrate,
dissolve rapidly in water, and provide good bleaching of stained textiles during
laundering a dispersion of 100g sodium-Dedecylbenzene-sulfoflate in 800g
molten 2-phenyl-4H-3,1-benzoxazin-4-one was prepared at 130 °C, cooled and
milled to give particles with av. diameter 0.5-1mm [219,235].
2-Alkyl and 2-aryl-4H-3,1-benzoxazin-4-ones are widely used in the synthesis
of polymeric materials and optical bleaching agents [41,127]. Some 4H-3,1-
benzoxazin-4- ones bearing sulfonylamino groups are used as fluorescent dyes
[181].
Recently, 4H-3,1-benzoxazin-4-one derivatives with (2-aryl) vinyl substituent at
2-position were reported as useful UV absorber having absorption in the long-
wavelength region for cosmetics [293].
(2,2‘-Di-(4H-3,1-benzoxazin-4-one))-m- or p-phenylenes were used for
improving the light-fastness of textile materials, where they are used for
increasing the light-fastness of textiles and producing textiles which protect the
wearer from the solar UV radiation [220].
2. Synthesis of 4H-3,1-benzoxazin-4-ones
4H-3,1-benzoxazinones comprise a relatively large group of substances which
have come to be known were synthesized as follows:
2.1 From anthranilic acids
By far the most popular and versatile route to the 3,1-benzoxazinone nucleus
relies on anthranilic acid or its derivatives as a convenient starting material.
2.1.1 Via the action of acid chlorides on anthranilic acid
2-Alky, -aryl and -aryalkyl 4H-3,1-benzoxazinenes 1 have been obtained by
heating anthranilic acid or substituted anthranilic acid with acid chlorides. Here,
a vast array of acid chlorides are either commercially available or easily
prepared.
Introduction
4
1 a-z12
The compounds thus obtained are collected in the following table
X Y R Reference
a H H -C6H5 [128, 36]
b H H -CH3 [315, 75]
c Br H -CH3 [266]
d H H -C3H7(iso) [121]
e H H -CH2COCH3 [96]
f H H -CH2C6H5 [96]
g H H -C3H7(n) [119, 126]
h H H -CH2CI [256]
i H H -C10H7(α) [88]
j Br Br -CH3 [161]
k H H
[110]
l Br Br -C6H5 [162]
m I H -CH3 [213]
n NO2 H -C3H7(n) [64]
0 CH3 H -C6H4C4H9(t)(4) [141]
p H H C4H3S [107]
q I H C6H5 [131]
r H H
[44]
s H/Br
Br/Cl
H/Br
H -C6H4.C1(4) [188]
t H/Br H/Br
C6H5-
-C6H4CI (o,
m,p)
[188]
u H H -C6H4.I(o) [148]
v I H -C6H5 [4]
w I H -CH2Cl [90]
x H H -C2H5 [30]
y NHSO2R H -CH3 [310]
z H H -C6H4.NHSO2R [51]
Introduction
5
X Y R Reference
z1 H H
[285]
Z2 CH3 H -C6H4.C4H9t(4) [141]
Z3 H H -CH=CH2 [176]
Z4 H H -C10H7(β) [210]
Z5 Br Br C4H3S [162]
Z6 Br/H Br/H -CH3 [171]
Z7 Cl Cl -C6H5 [214]
Z8 H OCH3
C6H4Br(4),
C6H4Br(2),
C6H4C1(3),
C6H4F(2),
C6H4C1(4),
C6H4C1(2)
[155]
Z9
H OCH3
- CH3, C2H5,
C4H9,
C6H5,
C6H4Br(4),
C6H4Cl(4),
- C6H4Br(2),
C6H4Cl(2),
C6H4F(2),
C6H4CH3(2),
C6H4(OCH3)(2)
[156]
z10
H Cl/CH3
- C6H4Br(2),
C6H4Cl(2),
C6H4F(2),
C6H4CH3(2),
C6H4(OCH3)(2)
[156]
F H
-CH2CH2ph,
Bu,
Ph,
[327]
z11 H H C4H3 O [193]
z12
2-
aminobenzoic
acid
Ph
CH3 H [61]
Introduction
6
Although these methods provide benzoxazinones in a straight forward manner,
the lack of a wide variety of readily available acid chlorides limits the generality
of this method. As a modification of literature methods [326,313], 2- aryl-4H-3,
1-benzoxazin-4-ones 5 were obtained via reaction of anthranilic acid with two
equivalents of an acid chloride in pyridine solution.
5 a-g
The compounds thus obtained are collected in the following table
X R Ref.
a H
Y= H, Cl, Br, Me,
OMe, CF3, NO2,
COOH(at o-, m-,p-)
[36,147, 141,173,133,239]
b H
[36,297,265,267]
c H [36]
d H
Y= H, Me, OMe, NO2
[36]
e H
[277, 183]
f H
Y H, 3-F, 2-F, 3-
OMe, 4-OMe, 2-OMe,
3-OH, 4-OH, 2,5-Di-
OH, 2-OH
[273]
g NO2 -C6H5 [175]
In contrast, the 3-chloro sulphonylbenzoyl chloride 6 reacts with 2 equivalents
of anthranilic acid to give N-(3-chlorosulphonylbenzoyl)anthranilamide (7),
which furnishes the 3-(4-oxo-4H-3,1-benzoxazin-2-yl)benzenesuphonyl chloride
(8a) on treatment with thionyl chloride. 4H-3,1-benzoxazinones 8b,c are
obtained on treatment of 8a with aniline and piperidine at 20 °C in acetonitrile
[296].
Introduction
7
On the other hand, 5-fluoroanthranilic acid reacts with acid chlorides 9 in the
presence of triethylamine and methylene chloride at room temperature to afford
10, which on heating with acetic acid anhydride for 1hour produces the 6-fluoro-
2-substituted benzoxazinones 11 [327].
The reaction of acid chlorides with anthrailic acids can be performed as a one-
pot reaction. Thus the reaction of substitute anthranilic acid with to 2-
substituted benzoyl chlorides 12 in presence of Et3N and CH2C12 followed by
addition of acetic acid anhydride and affords disubstituted benzoxazinones
13[261].
The compounds thus obtained are collected in the following table
X Y R R1 R2
a Br H CH3 Br H
b Br H CH3 C6H4.Cl(4) H
c H Br H H Br
d H Br H H C6H4.Cl(4)
e H H CH3 H H
Introduction
8
X Y R R1 R2
f OCH3 H OCH3 OCH3 H
g OCF3 H CH3 OCF3 H
If 4,6-dimethoxyanthranilic alkanoyl chlorides 14 in TEA and acid is reacted
with CH2CI2 at 40 °C, 4H-3,1-benzoxazin-4-one derivatives 15 is produced
[136].
5-Bromoanthranilic acid is cyclized with 2- naphthoyl and/or phenethyloyl
chloride by heating the mixture with DMPA and triethyl amine in DMF and
furnishes 16 [322]
Moreover, reaction of anthranilic acids 17 with synthesized acid chlorides 18
was carried out in boiling benzene followed by refluxing in acetic acid
anhydride to afford benzoxazinone derivatives 19.
The compounds thus obtained are collected in the following table
X Y R Ref.
a H H
[42]
b Cl Cl
[14]
2.1.2 Via the action of acid anhydrides on anthranilic acid
Simple 2-substituted derivatives 20 are best prepared by reacting an anthranilic
acid derivative with an appropriate anhydride at elevated temperatures. Lower
Introduction
9
molecular weight anhydrides are usually employed as the solvents
[57, 249, 243, 178, 23, 35, 111].
2-Methyl-4H-3,1-benzoxazin-4-one (1b) are obtained by heating anthranilic acid
with acetic anhydride [200].
Recently, 2-methyl-6-halo-4H-3,1-benzoxazin-4-ones 21 are obtained by
heating 5- haloanthranilic acid with acetic acid anhydride for two hours.
2-methyl-5,7-dinitro-4H-3,1- benzoxazin-4-one (22) is prepared in the same way
by generating 4,6-dinitroanthranilic acid (catalytic reduction of 2,4,6-
trinitrobenzoic acid) followed by heating with acetic acid anhydride [177].
Similarly, 2-(β-carboxyethyl)-4H-3, 1-benzoxazin-4-one (23) has been obtained
by heating anthranilic acid with succinic acid anhydride in n-butanol [119].
Introduction
11
Also co-solvents as chloroform, dioxane, toluene, and orthoesters are used
successfully as cyclizing agents [26, 45, 306].
In addition, a series of o-carboxymaleanilic acids 24 are prepared by reacting
anthranilic acid with maleic anhydride, methylmaleic anhydride, or
phenylmaleic anhydride, which intermolecularly dehydrated to afford
pyrrolobenzoxazinones 25. Which underwent solvolysis via refluxing with
anhydrous methanol furnishes 26 [40].
X Y Z
a H H H
b Cl H H
c Br H H
d I H H
e H Me H
f H H Me
g H Ph H
h H Me Me
i H o-C4H4 o-C4H4
Under identical conditions, o-carboxyfumaranilic acid afforded 2-
carboxyvinylbenzoxazinone 27 which does not further cyclized due to its cis-
geometry [40].
Introduction
11
2.1.3 Via reaction of anthranilic acid with aromatic carboxylic acid
A closely related synthesis of 2-phenyl-4H-3,1- benzoxazin-4-one 28 uses the
reaction of anthranilic acid with two equivalents of an ortho or para substituted
benzoic acid (X= H, Cl, Me, OMe, NO2) in the presence of tosyl chloride [255].
Starting from anthranilic acid on one hand and the aromatic carboxylic acids 29
on the other hand, where the preliminary chlorination to furnish the acid
chloride is not necessary when the reaction proceed to yield benzoxazinone
derivatives 30 a-o as a final product is performed in phosphoryl chloride under
nitrogen atmosphere [260].
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)
(j)
(k)
(l)
(m)
(n) (o)
Introduction
12
Recently, heteroarylbenzoxazinones 33 a-c were prepared by heterocyclization
of heterocarboxylic acids 32a,b with substituted anthranilic acids 31a,b. If the
benzoxazinone 33a is combined with 3-(dimethylamino) pyrrolidine gives 4H-
3,1-benzoxazin-4-one derivative 33e.
The compounds thus obtained are collected in the following table
R1 R
2 R
3 R
4 R Ref.
a Et H OMe H
[274]
b H CN H Me
[190]
c Et H OMe H
[274]
Another variation of this method uses the coupling of the pyrazole acid 34 with
anthranilic acids 35 in acetonitrile and triethyl amine in presence of
methanesulphonyl chloride to obtain the 4H-3,1- benzoxazin-4-one derivatives
36.
2.1.4 Reaction of substituted anthranilic acid with Boc-protected
amino acids
The interesting aminobenzoxazirione derivative 37 was readily prepared from
the reaction of equimolar quantities of 3-trifluoromethylanthranilic acid and
Bocprotected amino acid with two equivalents of isobutylformate in the
presence of N-methylmorpholine with complete retention of the chiral
information [66, 67].
Introduction
13
2.1.5 Reaction of substituted anthranilic acid with 2,2-dihydro
fluoroalkanoic acid
2-[(z)-1-hydrofluoro-1-alkenyl]-4H-3,1-benzoxazin-4-ones 38 are obtained via
condensation of 2,2-dihydropolyfluoro alkanoic acid with anthranilic acid or its
derivativesinthepresenceofN,N‘-dicyclohexylcarbodimide (DCC) in CH2C12
[194].
a-d e-j 38
a, R1=R2R3=H b, R1=H, R2=R3=OCH3
c, R1=R=H, R2=Cl d, R1=R3=Br, R2=H
RF, e=C5F11, f = CF6C1, g = C3F7,
h=CF2C1, I = CF2Br, j = CF3
2.1.6 Synthesis of Bis(411)-3,1-benzoxazin-4-one derivatives :-
Bis(4H)-3,1-benzoxazin-4-one derivatives 39 are prepared from interaction of
terephthaloyl chloride with diethyloxalate or anthranilic acid [201].
a, n= 0 in case of diethyloxalate
b,n=1 in case of terephthaloyl chloride which gave 2,2‘-p-phenylene bis-(6-
substituted)-3,1-benzoxazin-4-one.
General formula (39; R1, R2= C1-C10 hydrocarbyl, C1-C3 alkoxy, C1-C4 acyl,
halogen, nitro, Ar C6-C12 aromatic hydrocarbon group n= 0,1) were prepared
andusedaslightstabilizerforpolyesterfibers‘[201].
Similarly a sunscreen contains a cyclic imino ester (40) (R = divalent aromatic
hydrocarbyl) as a UV absorbent, has been obtained via interaction of 2,6-
naphthalene dicarboxylic acid chloride with anthranilic acid in pyridine [324].
Introduction
14
It is resistant to water, not readily soluble in organic solvents, fats, oils, and
nonirritating to the skin. It prevents skin rash and acts as skin conditioner.
2.1.7 From interaction of anthranilic acid with heterocyclic
compounds
2.1.7.1 From 4-arylidene-2-aryl-oxazoIin-5-one
2-substituted-4H-3,1-benzoxazin-4-ones 41 were obtained via interaction of 4-
arylidene-2-aryl- oxazolin-5-one with anthranilic acid in boiling butanol.
The compounds thus obtained are collected in the following table
X Ar Ar Ref
a H C6H4.(OCH3)(4) C6H5 [84]
b H C6H4.NO2(3) C6H5 [84]
c H C6H4.(OCH3)(4) C6H4.(OCH3)(4) [84]
d H C6H4.C10H7 (2) C6H5 [94]
e H C6H2.(OCH3)3(3,4,5) C6H4.Cl(2) [94]
f H C6H2.(OCH3)3(3,4,5) C6H4.Cl(2) [94]
g H C6H2.(OCH3)3(3,4,5) C6H5 [99]
h H C6H4.Cl(4) C6H5 [99]
i H C6H4C10H7(l) C6H5 [6]
j H 2-furyl C6H5 [6]
k Br C6H5 C6H5 [217]
2.1.7.2 From iminodithiazole
Iminodithiazole obtained from condensation of anilines with 4,5-dichloro-1,2,3-
dithiazolium. Chloride were reacted with a solution of anthranilic acid (in
Introduction
15
methylene chloride) in the presence of pyridine to produce 2-cyano-3,1-
benzoxazin-4-one (42). A similar reaction of using triphenyl phosphine instead
of pyridine yielded the analogous 3,1-benzothiazin-4-one 44. The delicate
intermediate iminodithiazole 43 can be isolated if four equivalents of anthranilic
acid are used without the addition of pyridine. Heating of 43 in toluene afforded
42, while treating 43 with two equivalents of triphenyl phosphine produces 44
[47, 48].
2.1.7.3 From (4H)-3,2-benzoxazin-4-one
2-substituted-4H-3,1-benzoxazin-4-ones 45 have been obtained when 1-
substituted-4H-3,2-benzoxazin-4- one derivatives were allowed to react with
anthranilic acid in boiling n-butanol.
Ar Ref.
a, -C6H3(CH3)2(3,4) [99]
b, -C6H4.C6H4(4) [100]
2.1.7.4 From 3- methyl-2-(ethoxycarbonylmethoxy) quinoxaline
Substituted-4H-3,1-benzoxazin-4-one 46, which bearing a hetaryl moiety at 2-
position, are synthesized via interaction of 2-(ethoxycarbonyl methoxy)-3-
methylquinoxaline with anthranilic acid in boiling butanol at 120 °C [210].
2.1.7.5 From 2-ethoxycarbonyl-4(3H)-quinazolin-4-one
Introduction
16
2-[4(3H)-oxoquinazol-2-yl]-(4H)-3,1-benzoxazin-4-one (47) are synthesized via
interaction of 2- ethoxycarbonyl-4(3H)-quinazolinone with anthranilic acid by
fusion at 170 °C or by refluxing in n-butanol for 3 hr [19].
2.1.7.6 From substituted coumarin
4H-3,1-benzoxazin-4-one derivative 49 is resulted from the interaction of
anthranilic acid with (2- oxo-2H-chromen-4-yloxy)acetyl chloride 48a or the
ester 48b in boiling ethanol [27].
a; R= Cl b; R= OEt
While, 4H-3,1-benzoxazin-4-one 51 bearing coumarin-3-yl moiety at position-
2 was obtained via interaction of 3-ethoxycarbonyl coumarin 50 with anthranilic
acid by fusion at 150 °C or refluxing in n-butanol [102].
Similarly, 2-cyanomethyl, acetonyl andlor ethoxycarbonyl-4H-3,1-benzoxazin-
4-one 52 were obtained via interaction of ethylcyanoacetate, ethylacetoacetate
and diethyloxalate with anthranilic acid in boiling butanol.
R Ref.
a -CH2CN [212]
b -CH2COCH3 [96]
c -COOC2H5 [19]
Introduction
17
2.1.7.7 From hetero-ring opening of furanone derivatives
Hetero-ring opening of the furanone derivatives 53 with anthranilic acid in
boiling butanol affords the 4H-3,1-benzoxazin-4-one derivatives 54 [284].
2.1.7.8 From hetero-ring opening of 1,3-dioxin-4-one derivatives
2-Substitutedphenylvinyl-4H-3,1-benzoxazin-4- one derivatives 56 were
synthesized via refluxing anthranilic acid with 2,2-dimethyl-6-phenyl-
[1,3]dioxin- 4-one derivative 55 in m-xylene, followed by dehydration [309].
2.2 From N-acylanthranilic acid
Starting from an N-acylanthranilic acid a variety of reagents can be used to
affect cyclodehydration to the benzoxazin-4-one.
2.2.1 Acetic anhydride as cyclizing agent
Acetic anhydride is the most widely used reagent for this purpose, the
cyclization can accommodate a wide variety of acyl groups (X = electron
donating or withdrawing group, R = alkyl, substituted phenyl, CH2Cl ,
CH(CH3)Cl , styryl , trifluoromethyl , phthalimidomethyl , COOEt , 2-thienyl ,
pyridyl or thiadiazole) [71,163].
Also, aromatic systems containing thionylamino functionality at position-2 was
introduced to obtain derivative 58 [15].
Introduction
18
More complex heterocyclic systems such as a coumarin can be introduced into
the 2-position of the benzoxazinone affording 59 [269].
Anthranilic acid can also be acylated at nitrogen with either diketene [72, 73] or
2,2,6-trimethyl-4H-1,3-dioxin-4-one (diketene acetone adduct) [63] to give 60
which when exposed to acetic anhydride cyclizes to the 2-acetonyl derivative
61.
2.2.2 Thionyl chloride as cyclizing agent
Refluxing a solution of substituted N-acylanthranilic acid 62 with a small excess
of thionyl chloride in 1,2-dichloroethane produces the benzoxazin-4-one
derivative 63 [144].
2.2.3 Vilsmeier reagents as cyclizing agent
Vilsmeier reagents generated front e.g. N,N-dimethyl formamide and oxalyl
chloride, were reacted with N-acetylanthranilic acid to produce the 2-(2‘-
dimethylamino)ethenyl-4H-3,1-benzoxazin-4-one (64a). Similarly, N-
Introduction
19
phenylacetyl anthranilic acid gave 2-(2‘- dimethylamino-1‗-phenyl)ethenyl-4H-
3,1-benzoxazin-4- one (64b) [46].
Reaction of N-acetylated anthranilic acids and oxalyl chloride alone give the
fused oxazolidine-4,5-dione (65) [46].
2.2.4 Cyanuric chloride as cyclizing agent
2-(N-phthaloylmethyl)-4H-3,1-benzoxazin-4-one 68 are prepared via reaction
of the acyl chloride derivative N-phthaloylglycine with anthranilic acid in
chloroform and N-phthaloylanthranilic acid 67 is generated. It reacted with
cyanuric chloride to form the final product [272].
2.2.5 Dicyclohexylcarbodiimide as cyclizing agent
N,N‘-dicyclohexylcarbodiimide (DCC) is used for dehydration of N-
acylanthranilic acid 69 to obtain the 2- ethoxycarbonylmethyl-4H-3,1-
benzoxazin-4-one 70. Where, N-acylanthranilic acid 69 was obtained via
reaction of anthranilic acid with diethylmalonate [303].
Introduction
21
Dehydration of N-acylanthranilic acid 71 to benzoxazinone 72 using DCC is
achieved in higher yield and shorter reaction time as compared to the conversion
with acetic acid anhydride as dehydrating agent [309].
2.3 From 2-methyl-4H-3,1-benzoxazin-4-one
2-styryl or substituted styryl-4H-3,1-benzoxazin-4-ones 73 have been obtained,
via interaction of 2- methyl-4H-3,1-benzoxazin-4-one with aromatic aldehydes
and /or ketones in the presence of anhydrous zinc chloride at 170 °C.
The compounds thus obtained are collected in the following table
X Y R Ref.
a Br H C6H5 , C6H4.OCH3(4),
C6H4.NO2(4),
C6H3(O2CH2)(3,4),
C6H4N(CH3)2(4),
-CH=CH-C6H5
[266]
b H CH3CO C6H5, C6H4.OH(4),
C6H4.NO2(3),
C6H4.OCH3(4), -CH=CH-
C6H5 , C6H3(O2CH2)(3,4)
[96]
c H C6H5 C6H4.OCH3(4), C6H4.OH(2),
C6H4N(CH3)2(4), -CH=CH-
C6H5
[92]
d H H OC6H4.C1(4) , C6H5 ,
C6H3(O2CH2)(3,4)
[101]
e H H C4H3O(2) [203]
Introduction
21
Similarly, 2-cyanomethyl-(4H)-3,1-benzoxazin-4- one has been reacted with
phthalic anhydride, succinic anhydride, phthalimide and succinimide to give the
benzoxazinone derivatives 74 [212].
R=
A more recent concept uses the idea of reaction of aldehydes with chloromethyl
benzimidazole, meanwhile the 2-[(2-aryl-1-chloro)vinyl]-4H-3,I-benzoxazin-4-
one 77 is obtained via interaction of 2-chloromethyl analog 75 with aldehyde 76
in presence of chlorotriethylsilane [262].
2.4 From isatoic anhydrides
Isatoic anhydrides are noted for their versatility in heterocyclic synthesis, so it is
no surprise that 4H-3,1- benzoxazin-4-one heterocycle can be obtained from the
closely related 2H-3,1-benzoxazin-2,4( 1H)-dione (78) system.
2.4.1 Reaction of isatoic anhydride with acid anhyd rides
When isatoic anhydride 78 is refluxed in acetic anhydride [297], acetic acid
anhydride/ pyridine [166, and 301] or stirred with trifluoro acetic acid
anhydride/pyridine at room temperature [321] the corresponding benzoxazinone
79 is isolated in high yield.
Introduction
22
2.4.2 Reaction of isatoic anhydride with acid chlorides
Likewise, refluxing a mixture of isatoic anhydride 78 and either cinnamoyl
chloride or oxalyl chloride in pyridine/toluene solvent produces the 2-styryl
analog 80 or the bis-3,1-benzoxazin-4-one 81 [166]. If the reaction with oxalyl
chloride carried out in benzene using anhydrous aluminium chloride or 4-
(dimethylamino)pyridine as an additive, the 2- chloroformyl derivative 82 is
isolated [301].
Isatoic anhydride also reacts with acid chlorides at elevated temperature to give
3,l-bezoxazin-4-one. Thus, heating compound 78 and benzoyl chloride results
the 2- phenylbenzoxazinone 1a [142, 143].
Coupling of trifluoromethyl-substituted isatoic anhydride 83 with pyrazole
acid chlorides 84 affords benzoxazinones 85 in modest yield.
Introduction
23
X Y R R‘ Ref.
a CF3 Me OCR3, CF3,
Br, Cl,
OCF2H,
OCH2CF3
[192]
B H H CF3 C6H5 [191]
Condensation of isatoic anhydride 86 with 3-substituted-acryloyl chloride 87
under basic condition yields the arylvinyl-4H-3,1-benzoxazin-4-ones 88 [293].
X R
a H Ph, CH3.C6H4(4), OCH3.C6H4(4), CI
.C6H4(4), Br.C6H4(4),
(OCH3)2.C6H3(2,4), C4H3O(2)
b Cl Ph, CH3.C6H4(4), OCH3.C6H4(4)
2.4.3 Reaction of isatoic anhydride with phosphoryl- stabilized
anions
Reaction of isatoic anhydride 78 with phosphoryl-stabilized anions bearing no
α-hydrogen atoms led to the formation of 3,1-benzoxazin-4-one. Consequently,
when compound 78 is allowed to react with the anion of ethyl2-
diethylphosphonopropanoate (89) or α-diethyl phosphono--butyrolactone 91
in benzene, it produces 90 and 92 respectively [204, 205].
2.5 Oxidation of indoles
2-substituted indoles 93 were readily oxidized With m-chloroperoxybenzoic
acid [55] or p-chloroperoxybenzoic acid [53] and the corresponding
benzoxazinone 94 are produced.
Introduction
24
A similar transformation is accomplished by the photooxygenation of 2-
phenylindole 95 in methanol using Rose Bengal as a sensitizer [129].
In a closely related transformation, the oxidation of 2-phenylindolenin-3-one
96 with m-chlorobenzoic acid in chloroform affords 1a [259]. Whereas,
oxidation of 4-dimethylamino analog 97 with hydrogen peroxide in N,N-
dimethylformamide furnishes 98 [10].
R
1a H
96 H
97 NMe2
98 NMe2
2.6 Miscellaneous
2.6.1 From β-(Triphenylphosphoranylidene)amino esters
β-(Triphenylphosphoranylidene)amino ester derivative 99 is treated with 1
equivalent of benzoyl chloride and triethylamine in acetonitrile and the
oxazinone derivative 100 is generated [314].
Introduction
25
2.6.2 From iminophosphorane
Similarly, treatment of iminophosphorane 101 with benzoyl chloride in
acetonitrile in the presence of small excess of triethyl amine yielded 7-nitro-2-
phenyl- 4H-3,1-benzoxazin-4-one (102) [314].
This reaction is used for the production of heteroannulated 3,1-benzoxazin-4-
ones, where the benzene ring is replaced with thiophene, thiazole, and
pyridazine [314].
2.6.3 From N-benzenesulphonylanthranilic acid
The self condensation of 2-molecules of N-benzenesulphonyl anthranilic acid
103 in polyphosphate ester (PPE) results in the formation of 2-substituted
phenyl-4H-3,1-benzoxazin-4-one 104 [312].
2.6.4 From thioamide derivatives
Heating thioamide derivative 105 in refluxing t-butylbenzene causes
cyclization to occur with loss of hydrogen sulphide and produces 2-pyrrolyl-
4H-3,1- benzoxazin-4-one 106 [195].
2.6.5 From electrochemical trichloroacetylanilides
The electrochemical reduction of several o-trichloroacetylanilides, 2-
CCl3CO.C6H4.NHCOAr (Ar =Ph, 4-MeC6H4, 4-MeOC6H4), on mercury pool in
acetonitrile, yields 4H-3,1-benzoxazin-4-ones 107 [216].
Introduction
26
2.6.6 CO2 Incorporation reaction using arynes
The CO2 incorporation reaction based upon three component assembly by the
use of arynes and imines produced benzoxazinones 109 . The reaction carried
out by in situ generated benzyne 108 which reacted with aryl imines under a
CO2 atmosphere (1 atm) [323].
R R‘ Ar
a 4- CH3 Me 2,4,6-(CH3)3.C6H2
b 4-F Me 2,4,6-(CH3)3.C6H2
c 6- CH3 Me 2,4,6-(CH3)3.C6H2
d 3-
OCH3
Me 2,4,6-(CH3)3.C6H2
e 4,5-
(CH3)2
Me 2,4,6-(CH3)3.C6H2
F 3,6-
(CH3)2
Me 2,4,6-(CH3)3.C6H2
g H H 2,4-(CH3O)2.C6H3
h H H 2,4-(CH3)2.C6H3
i H H 4-(CH3O).C6H4
j H H C6H5
k H H 1-naphthyl
l H H 2-thienyl
m H H 4-CF3.C6H4
n H Bn 4-CH3O.C6H4
o H n-Bu H
P H i-Pr H
2.6.7 From 2-(1H-1,2,3-benzotrizol-1-yl)phenylethanone
Homogenous flash vacuum pyrolysis reaction of 2-(1 H-1,2,3-benzotriazol-1
-yl)phenyl ethanone is considered as one-pot synthesis of 2-phenyl-4H-3,1
Introduction
27
benzoxazin-4-one (1a). Where the benzotriazole underwent acyl migration
followed by elimination of diazomethane and rearrangement of the intermediate
formed [218].
2.6.8 From heating of acetylanthranilic acid by microwave
The benzoxazinone 1b was obtained via heating of acetylanthranilic acid under
microwave heating conditions [300].
On the other hand, the 4H-3,1-benzoxazin-4-one derivatives 110 can be
obtained via applying optimized microwave reaction conditions to a variety of
anthranilic acids and both acyl chlorides (R1COCl) and carboxylic acids
(R2CO2H) in the presence of the coupling reagent triphenyl phosphite [193].
R R
1 R
2
H Ph Ph
H C4H3O(2) Bn
H (CH3)3CH
H C3H5
H Et
4- Me Me
4-Cl (CH3)2CHCH2
2-amino nicotinic
acid
Ph
A fast synthesis of 2-substituted-4H-3,1- benzoxazin-4-one 112 is achieved
from the reaction of acetic acid anhydride with 2-acylaminobenzoic acid 111
under microwave and solvent-free conditions [251].
Introduction
28
2.6.9 Thermolysis of 2-(3-benzoylthioureido)-4,5-dimethoxy benzoic
acid
2-benzoylamino-6,7-dimethoxy-4H-3,1-benzoxazin-4-one (113) is prepared by
thermal treatment of benzoic acid derivative [138].
The inactivation of Chymotrypsin and human Leukocyte elastase by compound
113 is reported [138].
2.6.10 Thermally induced cyclization of ketenimines
4H-3,1-benzoxazin-4-one 118 is prepared based on the thermally induced
cyclization of N-(2-benzyloxycarbonyl)phenyl keter.imines 117, generated
from the interaction of 2-azidobenzoyl chlorides 114 with benzylic alcohols
[13].
2.6.11 From o-iodoaniline
In all the syntheses of 4H-3,1-benzoxazin-4-ones presented so far the common
scenario begins with materials which have the amine and carbonyl carbon
R1 R
2 Ar
H Me 4-MeC6H4
CI Ph 4-OMe C6H4
3,4-(OMe)2C6H4
3,5-(OMe)2C6H4
Introduction
29
(which will ultimately become the 1- and 4-positions of the product) already
positioned appropriately on the benzene ring. An alternate strategy takes
advantage of carbonylation methodology which allows for the attachment of the
carbonyl function onto a simpler aniline derivative. This is elegantly
demonstrated by the reaction of an o-acylamidophenyl iodide 119 in the
presence of potassium carbonate and palladium catalyst under an atmosphere of
carbon monoxide which produces the benzoxazinone derivatives 120 [59].
A three-component reaction, using o-iodoaniline as the aromatic anchor, an aryl
iodide or vinyl triflate (as precursors of the substituent at 2-position), and carbon
monoxide to supply the 4-carbonyl, allows access to a variety of 2-aryl or 2-
vinyl-4H-3,1-bezoxazin-4-ones [59]. A good example of this methodology at
work is the reaction of o-iodoaniline with triflate 121 to give the steroidal
benzoxazinone 122.
Similarly, employing o-iodoaniline as building- block, unsaturated halides are
used as percursors of the substituent at 2-position of oxazinone nucleus, and
carbon monoxide in the presence of potassium carbonate and catalytic amount
of Pd(PPh3)4. Such a process can be easily fulfilled to afford 4H-3,1-benzoxazin-
4-one derivatives 123 containing an unsaturated unit, linked to C-2 [22].
Introduction
31
3. Reactions of 4H-3,1-benzoxazin-4-ones
4H-3,l-benzoxazin-4-one derivatives can be considered as semi-acid anhydrdes
formcd by cyclodehydration of acylanthranilic acids. They undergo many
reactions of true acid anhydrides, but at slower rate [117].
Electrophilic reactions on the benzene ring of the benzoxazinone nucleus are
rare and are probably unnecessary due to the plethora of diversely substituted
anthranilic acids which are available. We will concern on the remaining reactive
sites and feature the reactions at the C-4 and C-2 carbons of our heterocycle.
3.1 Reactions with Hydrogen nucleophiles
Benzoxazinone nucleus is susceptible to attack by hydride reagents as sodium
borohydride and tend to give varying mixture of 2-acylaminobenzyl alcohol 124
and N-alkylanthranilic acid 125 [24].
R = Me, t-Bu, CF3, Ph, styryl, 2-thienyl
In contrast, catalic hydrogenation of 2-methyl-4H-3,1-benzoxazin-4-one (1b) in
acetic acid affords only N-acetyl toluidine 126 [56].
Similary, hydrogenation of benzoxazinone 5a under neutral conditions resulted
in the initial reduction of C=N bond then cyclization with o-carboxylic acid
group and furnished the tetracycle 127 [56].
3.2 Reactions with Oxygen nucleophiles
The simplest and sometimes the most unwanted reaction of some 4H-3,1-
benzoxazin-4-ones is hydrolysis. Where, the 4H-3,1-beoxin-4-ones are
exceedingly labile to hydrolysis and the initial cleavage to N-acylanthranilic
acids parallels that of benzoxazoles to acylarninophenol.
Introduction
31
However, their sensitivities to hydrolysis vary greatly. 4H-3,1Benzoxazinone
(formanthranil) 128 and acetanthi-anil lb undergo cleavage by atmosphere
moisture. The higher 2- alkylbenzoxazinoes are increasingly stable and the 2-
aryl/and 2-styrylbenzoxaziones can be handled without special precautions [75].
Kinetic studies for hydrolysis of 4H-3,1 bcnzoxin-4-one in dilute buffers at 0.1
M ionic strength and D2O was reported. The bases in the buffers were catalysts
Sand the second order rate constants obeyed a Bronsted relation with isotope
effect on the OH term. Hydrolysis under acidic and basic conditions in O-
enriched H20 indicated attack at C2 and C4, respectively. R-substituted 2-phenyl-
4H-3, 1 -benzoxazin-4-one (R=H, p-Br, p-Me, p-MeO) showed Hammett p
values under acidic and basic conditions (-0.38 and +0.71). Strong acid media
inhibited hydrolysis of the phenyl and p-MeO derivatives in accordance with
extensive protonation of N1 and a lowering of the H2O activity with the
increased acidity [320].
Incorporation of a carboxylic acid at 8-position allows intramolecular
protonation of N1, which enhances susceptibility attack at C-2 and/or C-4 [80].
3.3 Reactions with nitrogen nucleophiles
Reaction of 4H-3,1-benzoxazin-4-ones with amines is the most interesting,
because of the wide range of heterocycles that can be produced either directly or
through further transformations of the initially formed products.
Introduction
32
3.3.1 Ammonlysis
The interaction of 4H-3,1-benzoxazin-4-one derivative 1p with ammonia in
ethanol produces compound 132 [76].
Ammonia (The simplest of amines) or ammonium hydroxide, when allowed to
react with benzoxazinone deriative 133 over a period of 1-3 hours, the
anthranilamide 134 is produced in good yield [233,230,317]. This in turn, can be
cyclized to 3-unsubstituted-4(3H)-quinazolone 135 under thermal conditions
(240-280 0C) or with acetic anhydride. quinazolone can also be produced after
longer reaction times with ammonium hydroxide ( 6-24h.) [199,233,230] or by
heating with formamide (170-175°C) [120, 119] or ammonium acetate at 130-
135°C [37,169].
X= H ,Cl ,Br ,Me
R = alkyl ,PhY ( Y =Br ,NHMe ) ,CH2CN
Boiling 4,6-dinitro-2-methyl-4H-3,1-benzoxazin-4-one (22) with aqueous
ammonia; suffered recyclization into the corresponding quinazolone derivative
136 [177].
2,6-Dimethyl-4(3H)-quinazolinone (137) is produced via interaction of 2,6-
dimethyl benzoxazinone 1z12 with 25% aqueous ammonia in ethanol at room
temperature for 48 hours. The obtained quinazolone 137 is converted to an
interesting 6-substituted quinazolone derivative 138, which is known as a
Cytotoxic active compound [61].
Introduction
33
In contrast, 4H-3,1-benzoxazin-4-one derivative 139 is formylated on treatment
with excess of formamide and yielded the N-formyl-quinazolinone derivative
140 [108].
3.3.2 Hydrazinolysis
3.3.2.1 Reactions with hydrazine hydrate
Heating 4H-3,1-benzoxazin-4-ones in neat hydrazine hydrate or in pyridine or
xylene solutions produces the 3-amino-4-quinazolones 141
[57,26, 306, 305, 185, 270,271, 208, 78, 283].
X=H, halo, Me, NO2
R=Me, Et, i-Pr, CF3, Ph, 2-furyl
It was found that, cyclization on both nitrogens of the hydrazine to form a 1,3,4-
benzotriazepin-5-one is not observed [305].
Similarly, heating benzoxazinone derivatives 1a,b with hydrazine hydrate in n-
butanol afford 3-aminoquinazolone derivatives 142 [211,210,158].
The quinazolone 142a is reacted with aromatic aldehydes and produces the
corresponding benzylidene aminoquinazolinone derivatives 143, which in turn
cyclized to thiazolone derivative 144 by its interaction with thioglycolic acid
[158].
Introduction
34
On the other hand, treatment of the benzoxazinone derivative 1z5 with hydrazine
hydrate in ethanol affords the (thienoylamino) dibromobenzamide 145 [162].
Compounds 1b and 1c undergo heteroring opening with hydrazine and give 2-
methyl-3 -amino-4(3H)-quinazolone. Compounds 146 condensed with aromatic
and aldehydes and give 2-styryl-3-benzyiidene imino-4(3H)-quinazolone
derivatives 147 (Ar=phenyl, substituted phenyl R=H, Br) [29].
R =H ,Br
Condensation of substituted 4H-3,1-benzoxazin-4-ones 148 with hydrazine
hydrate produce 3-amino-substituted quinazolinone 149. This compounds 149
treated with furan-2-aldehydes in the presence of acid catalyst forming
substituted-furyl-quinazolin-4(3H)-ones 150 [254].
X/Y =H,Br & R =Ph, Me, n-Pr&R‘=H,Me,NO2
A series of novel hydrazones 152 are synthesized by condensation of 3-amino-
6,8-dibromo-2-phenylquinazolin-4(3H)-ones 151 with different aromatic
aldehydes via cyclized intermediate 6,8-dibromo-2-phenyl-4H-3,1-benzoxazin-
4-one(11). The obtained hydrazones 152 are screened for its Antimicrobial
activity [242].
Introduction
35
Ar = Ph, C6H4.OCH3(4), C6H4.OH(2), C6H4.N(CH3)2(4), C6H4.NO2(3),
C6H4.CH3(4), C6H4.OH(4), C6H4.Cl(4), C6H4.NO2(4), C6H2(OCH3)3(3,4,5),
C6H3.OH(4).OCH3(3), -CH=CHPh
Also compound 1m reacts with hydrazine hydrate in ethanol and yields
aminoidometyl quinazolone 153, which reacts with phthalic anhydride and gives
phthalimidoquinazolinone 154. And with a second molecule of 6-iodo-2-methyl-
4H-3,1-benzoxazin-4-one 1m yields4-oxoquinazolinylquinazolinone 155 [213].
6,8-Dibromo-2-methyl-4H-3,1-benzoxazin-4-one (1j) reacts with hydrazine
hydrate in ethanol and gives 3-amino- 6 ,8-dibromo-2-methyl-4(3H)-
quinazolinone (156) [270,271].
Compound 156 reacts with chloro acetyl chloride and gives N-chloroacetyl
quinazolinone derivative 157a [270,271].
Introduction
36
a R=Cl e R=Et2N
b R=BuS f R=morpholinyl
c R=t-BuS g R= piperidinyl
d R=Me2N h R= N4 phenylpiperazinyl
Compounds 157b-h are prepared by eventual reaction of 157a with the
appropriate mercaptan or secondary amines, are tested for lethal toxicity in
mice, antifungal activity in vitro (Currularia lunata and Dreschlera halodis),
Analgesic activity in mice and Antiflammatory activity in rats [270,271].
In similar way as mentioned above, 6-fluoro-2- substituted 4H-3,1-benzoxazine-
4-ones 158 has reacted with hydrazine hydrate and compound 159 is generated
[325, 327].
R = PhCH2CH2, Bn, Ph, 2-thiophenemethylene
4H-3,1-benzoxazin-4-ones with additional reactive functionalities at 2-position
undergo further cyclization when exposed to hydrazine hydrate, and form a
variety of interesting heterocycles 163-167.
[38]
[46]
[169]
Introduction
37
[16,17]
[108]
On the other hand, when the reaction of 4H-3,1- benzoxazin-4-one 139 with
hydrazine hydrate is conducted in n-butanol, a mixture of 3,5 -bis-(4-
methoxyphenyl)-1H-pyrazole-4-carbonitrile (168) and N,N-bis-(4-
methoxybenzylidene)hydrazine (169) is obtained [108].
Ar = C6H4.OCH3(4)
3.3.2.2 Reaction with hvdrazine hydrate in presence of carbondisulphide
When the reaction of 4H-3,1-benzoxazin-4-one 1a with hydrazine hydrate is
conducted in the presence of carbon disulphide in alcoholic potassium
hydroxide, the 1,3,4-oxadiazolin-5-thione 170 is produced directly [164].
Introduction
38
3.3.2.3 Reaction with subsitituted hydrazines
Substituted hydrazines react likewise in solvents such as benzene, pyridine,
ethanol, or acetic acid to furnish 3-N-substituted quinazolone derivatives 171,
where R can be phenyl [213], acyl [5], (C= XNHR (X= O or S) [158], and
others [9,299].
R=Me, Et, i-Pr, CF3, Ph, 2-furyl
R‘=Ph,CH3CO, CONHR,CSNHR
4H-3,1-benzoxazin-4-one 139 is reacted with phenyl hydrazine in the same
manner like reaction with hydrazine hydrate, it gives a mixture of carbonitrile
172 and hydrazine derivative 173 [108].
Ar = C6H4.OCH3(4)
Hydrazinolysis of benzoxazinone derivative 1m using phenyl hydrazine
furnishes the quinazolinone derivative 174. It is used in synthesizing some
triazino-quinazoline derivatives 177 by introducing aromatic nuclei via Mannich
reaction with arylamines [279].
Introduction
39
R
Interaction of 2-methyl-4H-3,1-benzoxazin-4-one derivatives 178 with nalidixic
acid hydrazide 179 yield substituted 3,1-quinazol-4-one derivatives of nalidixic
acid 180, which exhibited inhibitory activity against A. hydrophila [135].
X= H ,I ,NO2
When 2-ethoxycarbonyl-4H-3,1-benzoxazine-4-one (181) treated with
substituted hydrazines 182, the hydrazones 183 are isolated [229].
R= Ph, COPh, COpy.
Combining 4H-3,1-benzoxazin-4-ones 184 acid substituted sulphonylhydrazides
185 devoid of solvents, followed by heating at 160 °C (oil bath) gave
compounds 186 as the major products [327].
R = phenethyl, Bn, Ph, 2-thiophene-methylene
R= 4-COOH.Ph, 3-COOH,Ph, 4-NHCOMe.Ph, 4-OCF3,Ph, 3,4-di-Cl.Ph, 4-
CN.Ph, 4-Cl.Ph, Bn, 3-N02-4-Cl.Ph, 4-t.Bu, 2,4-di-Cl.Ph
Reactions of acetonyl benzoxazinones 61 with methylhydrazine or various
phenylhydrazines affording the pyrazolyl anthranilic acids 187. Cyclization of
these intermediates with a mixture of phosphours pentoxide and polyphosphoric
acid providing the 4-hydroxypyrazolo [3,4- d]quinazoline 188 (Y= OH)
[63,288], whereas cyclization with phosphours oxychloride gives the 4-chioro
analog 188 (Y= Cl) [73,72].
Introduction
41
R = Me, Ph
X= H, Cl, I, Me, Et, OMe, CF3, COOH, NO2
Y= OH, Cl
Symmetrically disubstituted hydrazines are reacted with cyano derivative 189
with loss of HCN to produce 1,3,4- benzotriazepin-2,5-diones 190 [292].
R= Me, Et, i-Pr
3.3.2.4 Reactions with hydroxylamine hydrochloride
Reaction of 4H-3,1-benzoxazine-4-one derivatives 191 with hydroxylamine
hydrochloride in refluxing pyridine afford 3-hydroxy-4-quinazolinone
derivatives 192 [50, 92,121, 161].
R=Mc, Et, i-Pr, CF3, Ph, 2-furyl
X=H, halo, Me, NO2
3.3.2.5 Reactions with thiosemicarbazide and aminoguanidines
If heating 2-methyl-4H-3,1-benzoxazin-4-one (1b) with thiosemicarbazide in
acetic acid in the presence of fused sodium acetate, the conversion does not stop
at the thiocarbamide intermediate 193 but continues to cyclodehydrate providing
194 [159].
Introduction
41
In a similar fashion, refluxing 2- phenyl (or methyl)-4H-3,1-benzoxazin-4-ones
(1a or 1b) with aminoguanidine in pyridine to afford the amino derivatives 195
[71].
R=Me,Ph
3.3.3 Aminolysis
3.3.3.1 Reactions with primary nonaromatic amines
In many cases, acylanthranilamides are the products of the interaction of 4H-
3,1-benzoxazin-4-ones with primary amines (due to the weak nucleophilicity of
primary amines in comparison with aromatic amines and consequenyly depend
on the mode of attacking the benzoxazinone moiety).Reacion of 4H-3,1-
benzoxazinone 36 with isopropyl amine and/or methylamine in THF produced
the corresponding pyridylpyrazole anthranilic diamides 196. Compounds 196
have insecticidal potency and a Calcium mobilization threshold (CMT).
a; X= C1, Me
[190,192] Y=H,Cl
Z=CF3
R=i-Pr
b ; X=CH3
[191] Y=H,Cl,Br,I,CF3
Z=Br,CI, CF3, OCH3, OCF2H,
OCH2CF3 R = Me, i-Pr
Reactions of 4H-3,1-benzoxazin-4-one 1b with isopropyl amine and/or t-
butylamine produces N-acylanthranilamide 197 [114,118].
Introduction
42
a, R= -CH(CH3)2 b, R= -C(CH3)3
N-acylanthranilamide 197 requires temperatures above 200 °C to affect
cyclization into 3-substituted quinazolinone derivative 198 [115, 117].
Instead of using high temperature to effect cyclization, microwave-assisted
cyclocondensation is used to obtain 2,3-disubstituted quinazolinone 199 [179].
R1 = Me, Et R2 = Me, n-Bu, Et3N, ,
Simple straight-chain alkylamines as methyl and n-butyl amines react with
benzoxazinone 1b to afford 3-substituted-4-quinazolinones 200 [207].
R = Me, n-Bu
2-Methyiquinazolinone 200 can be easily homologated to styryl derivative 201
by refluxing it with an appropriate aldehyde [32].
R=Me, n-Bu Ar=Ph, naphthyl, 2-furyl
Introduction
43
4H-3,1-benzoxazin-4-one 202 furnishing 3-substituted quinazolin-4(3H)-one
204 via insertion of Boc-protected aminomethylpiperidine or 3-
aminomethylmorpholine, led to intermediate 203 which is deprotected and
subsequently is alkylated using reductive amination or nucleophilic substitution
conditions [261].
The compounds thus obtained are collected in the following table
X Y Z R R‘
a C6H4Cl(4) H CH2 C6H4CH3(2) Et,i-Pr,
(CH2)3CH-,
(CH2)2OCH3,
(CH2)2F,
EtCF3,n-Pr-
CF3
b C6H4Cl(4) H CH2 C6H4OCH3(2) Et
c F.C6H4 (4) H CH2 i-Pr Et
d H H CH2 C6H4CH3(2) i-Pr
e OCH3 H CH2 C6H4OCH3(2) Et
f OCH3 H CH2 C6H4CH3(2) Et
g F.C6H4 (4) H CH2 C6H4CH3(2) H, i-Pr
h Br H O C6H4CH3(2) Bn, H, i-Pr
i H C6H4Cl(4) CH2 C6H4OCH3(2) Et
3.3.3.2 Reactions with secondary amines
In a similar fashion, as isopropyl and/or t-butylamines are reacted with 4H-3,1-
benzoxazin-4-ones 205 and produce N-acylanthranilamides 206. Also secondary
amines such as dimethylamine, morpholine, piperidine, and pyrrolidine are
reacting and produce N-acylanthranilamides 206 [71].
Introduction
44
4H-3,1-benzoxazin-4-ones 207 with sulphonyl group introduced at 2-position
are reacting with piperidine under differenet reaction conditions leading to 208-
210. It gives an idea about the extent of the reactivity of the benzoxazinone
fragment, where the chlorosulphonyl group is more reactive than the
benzoxazinone fragment toward amines [294].
3.3.3.3 Reactions with alkylamines
3.3.3.3.1 Reactions with benzylamine
Treatment of benzoxazinone 1p with benzylamine in ethanol affords N-
acylanthranilamides 211 [76].
Introduction
45
On the other hand, treatment of 2-propyl-4H-3,1-benzoxazin-4-one (1g) with
benzylamine yields 3-benzyl quinazolinone 212 [126].
Bromination of quinazolinone 212 followed by addition of N,N-dimethyl
ethylene diamine produces 213. The latter quinazolinone 213 reacts with 4-
fluorobenzoyl chloride to furnish 214. Comnound 214 is a biologically active
compound and useful in trearment of Cancer, Hyperplasmia, Restenosis immune
disorders and inflammation [126].
2-Substituted acrylonitril-4H-3,1-benzoxazin-4-one 139 reacts with benzylamine
under different reaction conditions in order to give a mixture of N-
benzylquinazolinone derivative 215 and quinazolin-2,4-dione 216 [108].
3.3.3.3.2 Reactions with phenylethylamine
Search for novel drug-like Calcilytics identified a new quinazolinone derivative
217 formed via heating 4H-3,1- benzoxazin-4-one 1p with phenethylamine
[319].
Introduction
46
Similarly, refluxing 2-phenyl (or substituted phenyl)-4H- 3,1-benzoxazin-4-ones
218 with a 10 fold excess of phenethylamine for 2-3 hours at 200 °C produce the
corresponding 4(3H)-quinazolin-4-one derivatives 219 [273].
X = H, 3-F, 3-OMe, 4-OMe, 2-OH, 3-OH, 4-OH, 2,5-di-OH
Similarly, fusion of 2-(2-fluorophenyl)-substituted benzoxazinone 5f and
phenethylamine at 200 °C, resulted in the dominant nucleophilic displacement
of fluorine substituent with the amino moiety .For preservation of the 2-(2-
fluorophenyl) fragment, synthesis of the intermediate bisamide 220 was carried
out in pyridine at 120 °C followed by thermal cyclization to 2-(2-fluorophenyl)-
3 -phenethyl-3H-quinazolin-4-one (221) [273, 313].
Benzoxazinones 222 bearing fluorine at 5, 7, or 8- position are submitted to the
latter reaction with phenethylamine lead to amino-substituted quinazolinones
223 (where undesired nucleophilic displacement of the fluorine by the amine
Introduction
47
occurs), probably due to the reaction conditions (elevated temperature and
absence of solvent) [273].
a X=
5-F
Y= 5-PhCH2CH2NH
b X=
7-F
Y= 7- PhCH2CH2NH
c X=
8-F
Y= 8- PhCH2CH2NH
Applying microwave irradiation to the above benzoxazInone 222b results 7-
fluoro-substituted quinazolinone 224, whereas 5- and 8-fluoro-substituted
benzoxazinones 222a,c still produce products of nucleophilic displacement 223
a,c [273].
A series of 2-(2-hydroxyphenyl)-3-phenethylquinazolin-4(3H)-one 227 are
prepared in the same fashion starting from 2-(2-hydroxyphenyl) substituted
benzoxazinones 225 and phenethyl amines 226 [273].
Introduction
48
X Y
a 8-
Me
H
b 7-F H
c 7-Cl 3-F
d 6-Cl H
e 5-
Me
3-F
f H 3-Cl
g 6-
Me
H
X Y
h 5-
Me
3-F
i 6-F H
j 6-F 3-F
3.3.3.4 Reactions with anilines
Several experimental conditions for the reactions of anilines with 4H-3,1-
benzoxazin-4-ones are reported. The reactants can be combined neat at room
temperature [249], at elvated temperature ranging from 150- 220 °C
[287, 282, 152, 157] or at 150-180°C in the presence of zinic chloride
[87, 214, 7]. Alternatively, the reaction can be performed in solvents such as
pyridine [296,280], dioxane [90,16,17], acetic acid [206], dimethylformamide or
ethanol [90,154]. Substituted anilines 229 afforded quinazolinones 230 when
reacted with substituted benzoxazinones 228.
X=H, halo
R= Me, CH2CI, Ph, CH2Ph, COOEt
Y Ref.
a Halo [90]
b Me [154]
c OH [183, 281, 182]
d OMe [258]
e Phenoxy [33]
f NO2 [11,286]
g SO2NH2 [231,232,33]
h COOEt [23,207]
Introduction
49
3.3.3.4.1 Reactions with p-bromoanilines
p-Bromoaniline for example, reacts with benzoxazinone 1b in ethanol and
affords 3-(bromophenyl)-2-methyl-3H- quinazolin-4-one (231) [122].
Ar = Ph, 4-C1.Ph, 2-theinyl, 4-OMePh
3.3.3.4.2 Reactions with p-aminodiphenylamine
In similar fashion, interaction of 2-phenyl-6-iodo-4H-3,1-benzoxazin-4-one (1q)
with p-aminodiphenylamine yields 6-iodo-2-phenyl-3-(4‘-phenylaminophenyl)-
quinazolin-4-one
(233) [131].
3.3.3.4.3 Reactions with o-toluidine
Refluxing a mixture of benzoxazinone 1b and o-toluidine in toluene under
azeotropic conditions furnishes the CNS agent Methaqualone 234 [257].
The above reaction also can be conducted in acetic acid followed by
condensation of the produced quinazolinone 234 with 2-pyridinecarboxaldehyde
in the presence of zinc chloride and provided 2 [(pyridine-2-yI)vinyl]-3 -(2-
methylphenyl)-quinazolin-4(3H)-one (235), which is known as Piriqualone and
it was tested as anticonvulsant agent [318].
Introduction
51
Starting from substituted 2-methyl-4H-3, 1-benzoxazin-4-ones, a series of 3-(2-
methylphenyl)-2- [(2-pyridyl)vinyl] quinazolones 236 is obtained [318].
X = 6-CR3, 6-F, 6-Cl, 7-Cl, 8-Cl, 6,8-Cl2, 6-Br, 8-OCR3. 6,7-(OCH3)2
7-Carboxyquinazolone 237 is synthesized by mixing benzoxazinone 20 and o-
toluidine at room temperature for 3-4 hours [249].
3.3.3.4.4 Reactions with 2-substituted and/or 2,6-disubstituted anilines
A variety of 2-substituted and/or 2,6-disubstituted anilines interact with
substituted 4H-3, 1 -benzoxazin-4-ones to produce quinazolinone derivatives
238 [318].
Introduction
51
X Y Z X Y Z
a H F H g F Cl H
b H Cl H h F Br H
c H Br H i H H H
d H CF3 H j H CH3 CH3
e H OCH3 H k H Cl Cl
f F F H L F F F
In a similar fashion, a series of 3-(2-chlorophenyl)-2- substituted quinazolones
239 is prepared and their biological activity are tested. They are identified as
antagonist template for AMPA receptors (play an important role in
pharmacological studies of glutamate receptors) [65].
R
H CH3OCH2 piperidine
CH3 CH3CH2OCH2 (CH3)2CHNHCH2
CHO CH2F (CH3)2NCH2CH2N(CH3)CH2
CH2NH2 CN (C2H5)2NCH2
COOH COOCH3 (CH3)2NCH2
CH2OH C2H5NCH2 CH3NHCH2
AcOCH2 pyrrolidine
5,7-Dimethoxy-2-substituted benzoxazinones 240 are reacted with p-
methoxyaniline either via refluxing in xylene for 4 hours or in acetic acid at 60
°C for 24 hours and afforded 3-(4-methoxy phenyl)-4(3H)-quinazolinone 241
[ 136].
R = H, Me, Et, n-Pr, n-Bu, i –Bu
3.3.3.4.5 Reactions with anilines containing reactive function groups
3.3.3.4.5.1 Reaction with 2-cyanoanilines
Introduction
52
X= H, Cl , Me & Y = H, Cl, Me & R= Me ,n-Pr, i-Pr
3.3.3.4.5.2 Reactions with p-aminoacetophenone
Benzoxazinone 1m condenses with 4-amino acetophenone in n-butanol and
gives 2-methyl-6-iodo-3-(4‘- acetylphenyl)-quinazol-4-one (245a,b) [130].
a ; X= O
b; X= NNHCONH2
The semicarbazone 245b was obtained from 245a by refluxing with an
equimolar amount of semicarbazide hydrochloride in ethanol [130].
Cyanopyridin-2-(1H)-thione derivatives were obtained via the reaction of
arylmethylene-cyanothioacetamide (ArCH=C(CN)CSNH2) with the active
methylene carbonyl quinazolone 245b. An assay for Antitumor activity showed
that compound 246 (Ar= 4-OCH3C6H4) has a significant activity against Ehrlich
Acites Carcinoma tumor cells (in vitro) and displayed a significant percent of
the nonviable tumor cells to about 40% and 80% at concentration of 10 and
100mg, respectively [130].
Introduction
53
Ar= Ph, 4-pyridyl, 2-thienyl
3.3.3.4.5.3 Reactions with 4-hydroxyanilines
Treatment of 4H-3,1-benzoxazin-4-ones 247 with 4- hydroxyanilines 248 yield
the corresponding quinazolone 249 [245].
R = Me, Ph, CH2Cl, CH2Ph
a;R‘=H,X=Hb;R‘=Me,X=NO2
The latter quinazolones 249 react with 2-(4- diethylamino-2-
hydroxybenzoyl)benzoic acid (250) in the presence of sulphoric acid to produce
fluorans 251 [ 245].
3.3.3.4.5.4 Reactions with sulphanilamide
3-(4-sulphamoylphenyl)-4(3H)-quinazolin-4-ones (255; R = alkyl; R1 = H, Me,
halo; R2 = H, Cl, NO2 R
3= H, halo) are synthesized by condensation of
sulphanilamide with various 4H-3, 1-benzoxazin-4-ones 252. 2-amido-N-(4-
sulphamoyl phenyl)benzamides are isolated as reaction intermediates. Some of
quinazolone derivatives 255 showed significant anticonvulsant effects against
pentetrazoll- induced avulsions [111].
Introduction
54
Similarly, 1- [4-(4‘-oxo-2-methyl/ phenyl-4-(3H)-quinazolin-yl)-3-aryl ureas
(259; R = Me, Ph; R3
= H, Me; R2= H, Me; R
1,R
2= H, Br) are prepared by
reaction of corresponding quinazolinone-sulphanilamides 258 with aryl
isocyanates in the presence of K2CO3 in acetone solution. the corresponding
quinazolinones are obtained from interaction the corresponding 4H-3,1-
benzoxazin-4-ones 256 [221].
Both the oral and i.p. LD(50)
values for 259 in mice were 1600 to >2000 and 600
to 800 mg/Kg. This compounds were evaluated for their hypoglyceamic activity
against the streptozotocin induced diabetic rats. (259; R = Ph; R3= H, Me; R
1=
R2= H) decreased the blood sugar level significantly both in normal and
streptozotocin-induced diabetic rats. The other compounds showed significant
hypoglyceamic activity [221].
3.3.3.5 Reactions with amino heterocyclic compounds
Amino heterocycles such as pyridine, pyrimidine [277,31],pyrazole [247],
thiazole [277,113], or 1,3,4-thiadiazole [243, 298, 238] have been successfully
useful to prepare 3-heterosubstituted quinazolone with high biological activity
[11, 276, 187].
Introduction
55
Fusion of 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one 21b with heterocyclic
amines 260 produces 3-heterocyclic-2- methylquinazolone derivatives 261
[252].
a;R=5-indazolyl
b; R= 1-ethyl-5-pyrazolyl
Refluxing equimolar amounts of 2-methyl quinazolone 261 and benzaldehyde
in glacial acetic acid; the 3-heterocyclo-2-styrylquinazolinones 262 are
generated [253].
a; R= 5-indazolyl
b; R= 1-ethyl-5-pyrazolyl
Reaction of 4H 3,1-benzoxazin-4-ones 1a,c,m with 2- substituted-3-
aminoindoles 263 in dry pyridine produce 2- methyl-3 -(2‘-substItutedindol-3-
yl)-4(3H)-quinazolinone 264 [184].
X= H, 6-I, 6-Br
R= H, Me
Also 4H-3,1-benzoxazin-4-one 1b is reacted with 2,6- pyridindiamine to furnish
3-substituted quinazolone 265 [290].
Introduction
56
Synthesis of 3-(1‘,3‘,4‘-thiadiazolyl)-2-styrylquinazolin-4(3H)-ones (268) is
accomplished by a three-step procedure, the intermediate 3 -(1,3 4-
thiadiazoloIyl)-2-methyl quinazolinones 267 is obtained by refluxing 2-methyl-
4H-3,1-benzoxazin-4-one 1b with thiadiazole-amino derivatives 266
[168].
R Ar R Ar R Ar
a Ph 4-
ClC6H4
g Ph 3-
ClC6H4
m Ph 4-
pyridyl
b 4-
OCH3C6H4
4-
ClC6H4
h 4-
OCH3C6H4
3-
ClC6H4
n 4-
OCH3C6H4
4-
pyridyl
c 4-CH3C6H4 4-
ClC6H4
i 4-CH3C6H4 3-
ClC6H4
o 4-CH3C6H4 4-
pyridyl
d 4-ClC6H4 4-
ClC6H4
j 4-ClC6H4 3-
ClC6H4
p 4-ClC6H4 4-
pyridyl
e 3-ClC6H4 4-
ClC6H4
k 3-ClC6H4 3-
ClC6H4
q 3-ClC6H4 4-
pyridyl
f -CH=CHPh 4-
ClC6H4
l -CH=CHPh 3-
ClC6H4
r -CH=CHPh 4-
pyridyl
3.3.3.6 Reactions with diamines
3.3.3.6.1 Reactions with o-phenylenediamine
If refluxing benzoxazinone derivatives 269 with o-phenylenediamine in
chloroform, 2-substituted benzamidazoles 270 are formed. Conversally, heating
the above mixture in polyphosphoric acid at 200 °C provided 271 [250,163].
Introduction
57
R = Me, Ph, CH2Ph
If compound 271 is heated at 300 °C in a sublimation apparatus it
cyclodehydrated and benzimidazo quinazoline 272 is produced [250].
Refluxing a mixture of 2-ethyl-6-iodo-4H-3,1- benzoxazin-4-one (20b) and o-
phenylenediamine in acetic acid in the presence of fused sodium acetate resulted
the formation of tetracyclic compound 273 [30].
Cyclocondensatin of 2-aryl benzoxazinones 274 (R = Ph or substituted Ph)
with o-phenylenediamine catalyzed by orthophosphoric acid yield analgos
benzoimidazo quinazolinoneS 275 [237].
Introduction
58
X= H, 2-OH, 4-NO2
4H-3,1-benzoxazin-4-ones (276) reacts with o-phenylenediamine to afford 277
[250].
3.3.3.6.2 Reactions with ethylenediamine
2-Methyl-4H-3,1-benzoxazin-4-one 1b as well as 2- phenyl analog 1a are
reacting with ethylenediamine and produce the conesponding 3-functionalized
quinazolones 278 [239,114,118, 74].
R = Me, Ph
Analogs such as this have the added capability to react further and generated
more complex heterocyclic systems [250]. For example, heating quinazolinone
279 in acetic acid in the presence of fused sodium acetate, cyclodehydration
occurred and the imidazolo quinazoline 280 is generated [30].
3.3.3.6.3 Reactions with p-phenylenediamine
Interaction of 2-methyl-4H-3,1-benzoxazin-4-one (1b) with p-phenylenediamine
affords quinazolinone 281 [146].
Treatment of quinazolinone 281 with alkyl isocyanates followed by
cyclocondensation with phenacyl bromides or chloroacetic acid furnished
Introduction
59
quinazolinones 282 bearing heterocyclic moieties with high biological activities
[146].
a b c
R = NHCSNHR1 R = 3-alkyl- 4-
aryl-2, 3-
dihydrothiazol-2-
ylideneamino
R=3-alkyl-4-oxo-
thiazolidin-2-
ylideneamino R
1 = Me, Et, Bu, CH2Ph
3.3.3.7 Reactions with aminoacids
1 ,4-Disubstituted 3-[3‘-(2‘-phenyl-4-oxo-quinazolinyl)]- 2-azetidinones 284
[240],werepreparedbycyclocondensationofSchiff‘sbasesRN=CHR1 (same
R groups) with ketenes , the ketene was prepared by treating 1a (X =O) with
H2NCH2COOH to give 283b (X = NCH2COOH) which was converted to the
acid chloride 283c (X = NCH2COCl). Treatment of the acid chloride with Et3N
gave 283d (X = NCH=CO) in situ. Compounds 284 showed antiimplantation
acitivity in rats [240].
R R1
Ph Ph
4-
OMeC6H4
2-
CH3C6H4
2-NO2C6H4 3-
CH3C6H4
2-FC6H4 4-
ClC6H4
In the same manner, carboxyphenylquinazolones 286 has been obtained via
cyclocondensation of 2-aryl or alkyl-8- bromo-4H-3,1-benzoxazin-4-one 285
with p-aminobenzoic acid [225].
Introduction
61
X = H ,Br & R = Ph ,CH2Cl
2(phenyl/chloromethyl)-3-[4-(N,N-disubstituted amino carbonyl)Phenyl]-8-
substituted 4(3H)quinazolones 287 are synthesized by treating
carboxyquinazolinone 286 with SOCl2 in benzene and with the different
secondary amines. All quinazolinones 287 are screened for toxicity, central
nervous system, cardiovascular and anti-inflammatory activites. Most of these
compounds are found to be non-toxic and stimulant in nature. Some of this
compounds also exhibited cardiovascular and anti-inflammatory activities
[225].
X = H, Br
R = Ph, CH2Cl
R1R2N = morpholino, N-Me piperazino, Et2N, (HOCH2CH2)2N, piperidino,N-
phenylpiperazino
3.3.3.8 Reactions with aminoalcohols
2-Methyl-4H-3,1-benzoxazin-4-one 1b reacts with ethanolamine to produce the
corresponding 3-hydroxyethyl quinazolone 289 [71].
Heating of the resulting quinazolinone 289 with benzaldehyde yields the styryl
derivative 290. Epoxidation of the double bond, then treatment of the product
with sodium methoxide afforded 291 as a result of intramolecular attack of
ethanol group on the epoxide [81].
Introduction
61
Heterocondensed quinazolones 1 ,4-oxazino[3 ,4-b] quinazolin-6-one 292 has
been obtained (chloromethyl)-4H-3,1 -benzoxazin-4-one 1h with ethanol amine
followed by base-catalyzed cyclization [227].
3.3.3.9 Reactions with Schiff’s bases
Condensation of methylnaphthoxazinone 293 with ArCH=NAr‘ (Ar, Ar‘
substituted phenyl) in acetic acid yield benzoquinazolones 294 [186].
Similarly, compounds 297 are prepared by reaction of 4H-3,1-benzoxazin-4-one
derivatives 295 with Schiff‘s base 296. Compounds 297 are tested for
Anthelmintic, Virucidal and Bactericidal activity [278].
R = Me,Ph
R1 = 3-NO2, 4-OH, 4-NMe2, 2-OH, 4-Cl
R2 = H, Br
R3= H, Br
3.3.3.10 Reactions with azines
6- Bromo-2-methyl-4H-3,1-benzoxazin-4-one (1c) undergoes hetero-ring
opening followed by recyclization and condensation when treated with azines
298 and yielded 3-arylideneamino-substituted quinazolin-4-(3H)one 299. The
reaction involves a cleavage of the azine into its amine and arylidene moieties
which are smoothly incorporated into 1c via nucleophilic attack of the amine at
position-4 and condensation of the aldehyde with a reactive methyl group at
position-2 respectively [77].
Introduction
62
R = H, 4-OMe
3.3.3.11 Reactions with sodium azide
Treatment of 4H-3, 1-benzoxazin-4-ones 300 with hydrazoic acid (generated
with sodium azide in acetic acid) [163, 203, 28, 119, 109, 43, 86] or directly
with sodium azide in dimethylformamide [132] resulted in the formation of the
tetrazolyl benzoic acids 301.
X = H, Me, Br
R= H, Me, pr, ph, styryl, 2-thienyl
Reaction of compound 1z5 with HN3 gave the tetrazole 302 along with the
benzimidazolone 303 [162].
3.3.4 Reactions with carbon nucleophiles
3.3.4.1 Reactions with Grignard reagents
The benzoxazinone 1b reacts with Grignard reagents in a fashion determined by
the manner in which the reaction is carried out [315].
Introduction
63
While this benzoxazinone 1b reacts with cyclohexyl magnesium bromide in
THF to afford ketone 306 [62].
6,8-Dibromo analog 1j reacts with Grignard reagent and provide the unexpected
products 307 [196].
a; Ar = Ph b; Ar = CH2Ph
On the other hand, 2-phenyl-4H-3,1-benzoxazin-4-one 1a on reaction with
phenyl magnesium bromide by either the normal or inverse addition method
providing only 2- benzamidphenyl diphenyl carbinol 308 and its dehydration
product 2,4,4-triphenyl-3,1-benzoxazone 309 [12].
Similarly, 2-methyl-7-methoxy-4H-3, 1-benzoxazin-4-one reacts with p-
methoxyphenyl magnesium bromide to give 2-acetamido-4,4-
dimethoxybenzophenone [150].
6,8-Dibromo-2-phenyl-4H-3,1-benzoxazin-4-one (1I) reacts with different
Grignard reagents affording different products 310-312 depending on the nature
of the reagent and not on the reaction conditions [163].
Introduction
64
R = Et, 4-OMePh
Benzoxazinones 313 reacting with pyrrolyl Girgnard reagent followed by
hydrolysis to afford 2-amino-5- chlorophenyl-2‘-pyrrylketone 315 which is used
as a key intermediate in the synthesis of HIV Tat-Antagonists [226].
6-Halo-2-methyl-4H-3, 1-benzoxazin-4-one 316 reacts with Grinard reagent 315
and produces ketone 318, which by hydrolysis gives the amines 319 and 320
[268].
X = F, Cl, Br
Introduction
65
The benzoxazinone 321 is reacted with Grignard reagents and gave the carbinols
322 which are identified as o-(cinnamoylamidophenyl)diarylcarbinols [Error!
eference source not found.].
As a point of interest, 2-p-tolyl and/or p-chlorophenyl-4H-3,1-benzoxazin-4-
ones 323 are reacted with PhMgBr or CH3I and gave the carbinols o-
[HOC(R1)2] C6H4NHCOR [324;R
1= CH3, C6H5; R =C 6H4.CH3(4), C6Cl(4)]
which on heating with Ac2O-AcONa are cyclized to 4,4-(diphenyl or dimethyl)-
2-(p-tolyl or p-chlorophenyl)-3,1-benzoxazines 325 [329].
Reaction product 326 of benzoxazinone 1b and 4-chlorophenylmagnesium
bromide are treated with sodium ethoxide and are cyclized to the 4-
phenylcarbostyril 327 [151,197].
Bezoxazinone 1b reacts with 3,5-dimethylphenyl magnesium bromide and
produces 328a. The acyl group of 328a is removed under acidic conditions and
resulting 2- aminobenzophenone 328b. It condenses with methyl acetoacetate to
afford the quinoline 329, which is then elaborated by using Wittig methodology
to the 4-arylquinolin heterocycle 330. Compound 330 comprises the
hydrophobic domain of reductase inhibitors [316].
Introduction
66
Cardiotonic bemarinone, 5,6-Dimethoxy-4-methyl-2(1H)- quinazolinone 333 is
readily prepared from 4H-3,1-benzoxazinone 331 [70].
Addition of 2-methyl benzoxazinone 1b to an excess of t-butyl magnesium
chloride produces the secondary alcohol 334. The first equivalent of Grignard
reagent adds normally to 1b to generate N-acetylbenzophone derivative, then the
second equivalent of the reagent instead of adding to the newly formed ketone, it
reduces the keto group presumably because of highly steric interactions between
both ketone and organometallic [328].
BisGrignard reagents such as 335 add to 2-methyl benzoxazinone 1b to give
tertiary alcohol 336 [60].
Introduction
67
4H-3,1-Benzoxazin-4-ones 337 have bulky group at 2- position also react with
Girgnard reagent PhMgBr and produce compound 338 [263].
3.3.4.2 Friedel-Crafts reactions
2-Phenyl-4H-3, 1 -benzoxazin-4-one 1a and cyclohexyl-(4H)-3,1-benzoxazin-4-
one 339 are reacted with toluene in the presence of anhydrous AICl3 under
Friedel-Crafts conditions to give 2-benzamido and 2-cyclohexylamido-p-methyl
benzophenone 340 [265,267].
6, 8-Dibromobenzoxazinone 1I is submitted to arylation by applying Friedel-
Crafts reaction conditions, benzophenone derivatives 341 are afforded.
Compound 341a is reacted with hydroxylamine hydrochloride to yield oxime
342 [163].
Introduction
68
Ar = Ph, 4-CH3C6H4, 3,4-di-MeC6H3, 2,4-di-MeC6H3, 2,6.di-MeC6H3
In contrast, 6,8-dibromo-2-methyl-4H-benzoxazin-4-one 1j arylated in different
fashion; where it reacts with hydrocarbons namely, benzene, ethylbenzene, m-
and p-xylene to afford either two benzophenone derivatives 343 and 344 in case
of less bulky hydrocarbons (benzene, ethylbenzene) or only one product 345 in
case of more bulky m- and p-xylene [196].
R = 3-Me, 4-Me X = H, Et
Also 4H-3,1-benzoxazin-4-ones 41 with bulky groups at 2-position arylated
when submitted to react wits hydrocarbons under Friedel-Crafs reaction
conditions producing benzophenone derivatives 346.
Ar Ar‘ Ref.
a 4-OCH3C6H4 3-NO2C6H4 3-indolyl [86]
b 1-naphthyl 2-furyl 2,4-di-MeC6H3 2,5-di-MeC6H3 [6]
3.3.4.3 Reactions with active methylene containing compounds
Reaction of benzoxazinones with active methylene containing compounds
provide a variety of interesting results. Heating the benzoxazinones 347 with
diethyl malonate, ethyl cyanoacetate, or ethyl acetoacetate in dry benzene
produce.oneandthesameproduct348astheconsequenceofthelossoftheR‘
group [210, 265,26792, 212].
Introduction
69
z
R = Ph, CH2Ph, CH2CN, 2-naphthyl
R‘=COQEt,CN, COMe
An analogous reaction of thienyl derivative 1p with ethyl cyanoacetate
affording the cyclized product 349 [163].
Under the same conditions, benzoxazinone 1b with malononitrile and a mixture
of 350 and 351 is furnished [209].
Using potassium t-butoxide to generate the anion of the active methylene and
running the reaction at room temperature, allow the R‘ group to be retained
giving compound 352. That in turn, can be cyclized to the 4-hydroxy-2-
quinoline 353 with either sodium alkoxide or 8% alcoholic hydrochloric acid
[79].
R = COOEt, CN, COMe, SO2Me
Recentely, [274] showed that the hit-to-lead optimization of the HNE inhibitor
5-methyl-2-(2-phenoxy-pyridin-3-yl)-benzo[d][1,3]oxazin-4-one is described. A
structure–activity relationship study that focused on the 5 and 7 benzoxazinone
positions yielded the optimized 5-ethyl-7-methoxy- benzo[d][1,3]oxazin-4-one
core structure. 2-[2-(4-Methyl-piperazin-1-yl)-pyridin-3-yl] derivatives of this
core were shown to yield HNE inhibitors of similar potency with significantly
different stabilities in rat plasma.
Introduction
71
More recently, Waisser et al. [311] showed that the new 3-benzyl-4-thioxo-2H-
1,3-benzoxazine-2(3H)-ones and 3-benzyl-2H-1,3-benzoxazine-2,4(3H)-
dithiones were synthesized. The compounds were tested for in vitro
antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium
kansasii and Mycobacterium avium. The replacement of the carbonyl group by
the thiocarbonyl group increased the antimycobacterial activity. The most active
derivatives were more active than isonicotinhydrazide (INH). The cytotoxicity
and the antiproliferative activity were studied as well.
DISCUSSION
INTRODUCTION
Studies on 4H-3,1-Benzoxazin-4-ones
Discussion
72
DISCUSSION
1. Synthesis and reactions of N-(2-(4-chlorophenyl)-1-(4-oxo-
4H-benzo[d][1,3]oxazin-2-yl)vinyl)-2-(1,3-dioxoisoindolin-2-
yl)acetamide The present work deals with synthesis of N-(2-(4-chlorophenyl)-1-(4-oxo-4H-
benzo[d][1,3]oxazin-2-yl)vinyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide (2), as a
key starting material for many benzoxazinone derivatives.
It is well known [105] that 2-substituted 4(H)-3,l-benzoxazin-4-ones undergo
ring opening by moisture and many research groups have provided the
correlation of stability of benzoxazinones with various stryl derivatives in
position-2.
Thus compound (2) was prepared by treatment of anthranilic acid with (Z)-2-
((4-(4-chlorobenzylidene)-5-oxo-4,5-dihydrooxazol-2-yl)methyl)isoindoline-
1,3-dione (1).
1.1 The structure of compound (2) was established from the following:
1. Correct analytical data.
2. Infrared spectrum of (2) exhibited absorption bands at 1614 cm-1
( CO of
α,β- unsaturated amide), at 1774-1720 cm-1
( CO of benzoxazinone and
CO of cyclic imide) and at 3475, 3370 cm-1
( NH) .
3. The H1-NMR spectrum of (2) (; DMSO-d6) showed signals at 4.45(s,
2H, NCH2CO), at 6.75 (s, 1H, olefinic proton), at 7.22-7.91 (m, 12H, Ar-
H) and at 9.08 (s, 1H, NH) .
4. The mass spectrum of (2) (cf. Figs.3 and chart 1) showed the molecular
ion peak [M]+.
m/z = 485 and the molecular ion peak [M+2]+.
at m/z =
487 .
Discussion
73
Table 1 The mass spectrum fragmentation of compound (2)
m/z abundance
485 0.17
353 0.15
355 0.09
325 0.15
327 0.11
282 0.23
284 0.10
171 0.26
160 100.00
146 0.90
132 19.52
102 2.84
Discussion
74
Chart 1
Discussion
75
1.2 Chemical proven of compound (2)
1.2.1 Reaction with amines
It has been reported that 2-substituted (4H)-3,1-benzoxazin-4-ones reacted with
primary amines, amino acids or aminophenols in boiling ethanol to give 2-
substituted)-carbamoyl phenyl acetanilides [291].
R`NH2
CONHR`
NHCOR
- CH2Ph
- CH = CHAr
N
O
OC
R
R
The present investigation deals with the reaction of (2) with methylamine,
ethylamine, butylamine, hexylamine, glycine, p-anisidine and o-
phenylenediamine in boiling ethanol to give the corresponding 2-(substituted)
carbamoyl phenyl acetanilides (3a-h).
The formation of (3a-h) may be interpreted from the fact that amines or amino
acids react via the mechanism outlined below, in which the nucleophilic attack
by lone pair of electrons on the nitrogen of amino group upon carbon of
carbonyl group in benzoxazinone nucleus took place leading to ring opening of
the heterocyclic ring.
Discussion
76
R
R'NH2
NHCOR
H-
+
N = C - R`
CONHR
C - NH2R
+
- +H, -H+ +
N = C - R`
OH
CONHR'
N
O
O O
N
O NR
2
R`
N
O
O
N
3
The structure of (3a) was proved from:
1. Correct analytical data.
2. Infrared spectrum showed bands for compound (3a) at 1647 cm-1
(CO
of acyclic amides), at 1774-1713 cm-1
( CO of cyclic imide) and at
3317, 3133 cm-1
( NH) .
3. The mass spectrum of (3a) (chart 2) showed the molecular ion peak
[M]+.
m/z = 516.45 (0.02) and the molecular ion peak [M+2]+.
at
m/z = 518.5 (0.02).
Table 2 mass spectrum fragmentation of compound (3a)
m/z abundance
518.50 0.02
516.45 0.02
356 0.02
313 0.07
202 0.18
177 0.11
160 100.00
134 4.78
132 20.16
104 44.21
76 50.68
Discussion
77
Chart 2
Discussion
78
The structure of (3b) was proved from:
1. Correct analytical data.
2. Infrared spectrum showed bands for compound (3b) at 1645 cm-1
(CO of acyclic amides), at 1774-1715 cm-1
( CO of cyclic imide)
and at 3473, 3220 cm-1
( NH).
3. The H1-NMR spectrum of (3b) (; DMSO-d6) showed band at
1.2(t, 3H, CH3), at 4.1(q, 2H, CH2), at 4.43(s, 2H, NCH2CO), at
6.74(s, 1H, olefinic proton), at 7.2-7.92 (m, 12H, Ar-H) and 9.80-
10.38(s, broad, 3H, 3×NH) disappeared by addition of D2O .
The structure of (3c) was proved from:
1. Correct analytical data.
2. Infrared spectrum showed bands for compound (3c) at 1645 cm-1
(CO of acyclic amides), at 1774-1719 cm-1
( CO of cyclic imide) and
at 3360 cm-1
( NH).
3. The mass spectrum of (3c) showed the molecular ion peak [M+1]+.
at
m/z = 560 (50%) and the molecular ion peak [M+2]+.
at m/z = 561 (20%).
The structure of (3d) was proved from:
1. Correct analytical data.
2. Infrared spectrum showed bands for compound (3d) at 1641 cm-1
(CO of acyclic amides), at1774-1719 cm-1
( CO of cyclic imide) and
at 3475, 3240 cm-1
( NH).
The structure of (3e) was proved from:
1. Correct analytical data.
2. Infrared spectrum showed bands for compound (3e) at 1650 cm-1
(CO of acyclic amides), at 1774-1720 cm-1
( CO of cyclic imide) and
at 3448, 3350cm-1
( NH).
The structure of (3f) was proved from:
1. Correct analytical data.
2. Infrared spectrum showed bands for compound (3f) at 1640 cm-1
(CO of acyclic amides), at 1774-1712 cm-1
( CO of cyclic imide) and
at 3360 cm-1
( NH) and at 3300-2400 cm-1
( OH broad).
The structure of (3g) was proved from:
1. Correct analytical data.
2. Infrared spectrum showed bands for compound (3g) at 1644 cm-1
(CO of acyclic amides), at 1774-1716 cm-1
( CO of cyclic imide) and
at 3455, 3360cm-1
( NH).
Discussion
79
The structure of (3h) was proved from:
1. Correct analytical data.
2. Infrared spectrum showed bands for compound (3h) at 1640 cm-1
(CO
of acyclic amides), at 1774-1711 cm-1
( CO of cyclic imide) and at
3330, 3310cm-1
( NH).
1.2.1 Hydrazinolysis
Recently [2], it has been shown that the reaction of 3,l-(4H)-benzoxazinones
with hydrazine hydrate affected the fission of the heterocyclic ring. This
promoted us to study the proclivity of N-(2-(4-chlorophenyl)-1-(4-
oxo-4H-benzo[d][1,3]oxazin-2-yl)vinyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide
(2) towards hydrazines such as hydrazine hydrate and phenylhydrazine.
Hydrazinolysis of (2) with an excess amount of hydrazine hydrate gave the
hydrazide derivative (4a). On the other hand, reaction of (2) with phenyl
hydrazine, yielded quinazolinone derivative (4b).
The infrared spectrum of (4a) exhibited bands at 1617cm-1
( CO of α,β-
unsaturated amide), at 1774-1720 cm-1
( CO of cyclic imide) and at 3445 cm-1
( NH) .
The mass spectrum of (4a) showed the molecular ion peak [M]+.
m/z = 549
(16.7%) .
The infrared spectrum of (4b) exhibited bands at 1646 cm-1
(CO of cyclic and
acyclic amides), at 1774-1714 cm-1
( CO of cyclic imide) and at 3460-3380 cm-1
( NH).
The mass spectrum of (4b) showed the molecular ion peak [M-2]+.
m/z = 574
(40%) .
Discussion
81
2. Base catalyzed of 3,1-(4H)-benzoxazinone (2) with active
methylene compounds
Sammour et al [1] reported that 2-phenyl-3,1-benzoxazinone reacted with ethyl
acetoacetate to give o-ethyl-o-benzamido benzoyl acetate.
O
C6H
5
+CH
2COOC
2H
5
R
C - CH2COOC
2H
5
NHCOC6H
5R = CH
3CO
pyridineN
ON
O
In the present investigation, the reaction of (2) with ethyl acetoacetate gave
carbethoxy 3,4-dihydro-l,4-quinolinone derivative (5) .
O+ CH
3COCH
2COOC
2H
5
R
pyridine
R
COOC2H
5
N
O
N
O
(2)(5)
This result can be explained by the opening of the heterocyclic ring with the
carbanion of active methylene group followed by ring closure with
deacetylation.
The following support the structure assigned for the product (5)
1. Correct analytical data.
2. Infrared spectrum which showed bands at 1611cm-1
of ( COofα,β-
unsaturated amide), at 1725cm-1
( CO of ester), at 1774 ( CO of
imide) and at 3479 cm-1
( NH) .
3. The H1-NMR spectrum of (5) (; DMSO-d6) showed band at 1.2-
2.49 (m, with interference, 5H, COOCH2CH3), at 4.42 (s, 2H, NCH2),
at 3.37(s, 2H,CH2), at 6.74(s, 1H, olefinic proton), at 7.89- 7.91 (m,
12H, Ar-H) and 9.5-10.2 (s, broad, 1H, NH) disappeared by
addition of D2O .
3. Action of sodium azide Benzoxazinone (2) reacted with sodium azide in boiling acetic
acid and yielded 2-(5-(2-(4-chlorophenyl)-1-(2-(1,3-dioxoisoindolin-2-
yl)acetamido)vinyl)-1H-tetrazol-1-yl)benzoic acid (6).
Discussion
81
O+
R
NaN3
CH3COOH COOH
NC
R
N N
N
N
O
(2) (6)
The formation of (6) possibly takes place according to the following
mechanism:
COOH
NC
R
N
N
N
O
R
C - OH
N = C - R
HN3
+
N - N = N+-
C
N N
N
R
+
-
C - OH
N
N
O O
O
(2)
(6)
The infrared spectrum of (6) was consistent with the proved structure which
exhibited bands at 1111 cm-1
attributable to tetrazole nucleus, at 1614 cm-1
(
COofα,β- unsaturated amide), at 1718 ( CO of carboxylic), at 1774-1760cm-1
(due to coupling carbonyl bands of cyclic imide), at 3455, 2928 cm-1
( OH and
NH) .
The H1-NMR spectrum of (6) (; DMSO-d6) showed signals at 4.55(s, 2H,
NCH2CO), at 6.85 (s, 1H, olefinic proton), at 7.25-8.20 (m, 12H, Ar-H) and at
9.98-10.69(s, broad, 1H, NH) and at 13.84 (s, 1H, OH) .
4. Friedel-Crafts reaction
2-Substituted-4H-3,l-benzoxazinones reacted with AlCl3 in hydrocarbons under
the Friedel-Crafts condition reaction to give 2-aryl (alkyl) imido (substituted)
benzophenones [3].
Discussion
82
O
R NHCOR
AICI3
Ar-H
COAr
N
O
Thus,N-(2-(4-chlorophenyl)-1-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)vinyl)-2-
(1,3-dioxoisoindolin-2-yl)acetamide (2) reacted with benzene, toluene in the
presence of anhydrous aluminium chloride under Friedel-Crafts conditions to
give o-substituted phenyl aryl ketone (7a,b) .
O
R NHCO - RAICI
3
C - ArAr - H
b, C6H
4CH
3
a, C6H
5
N
O O
Ar
(2)
=
(7)
The reaction possibly takes place according to the following mechanism:
O
R
AICI3
N
O
O
R
AICI3+ - O
R
AICI3
+
+
- AICI3, -H, +H
-
NHCO-R
- OAICI3
R
+
N = C
R
OH
N
O
N
O
C
C
O
C-Ar
ArH
O
C - Ar - H
N
O
C
C-Ar
(7)
The structure of (7a,b) were confirmed from their infrared spectra which showed
bands at 1675-1657cm-1
( CO of ketone and ,-unsaturated amide), at 1774-
1725cm-1
( CO of cyclic imide) and at 3401,3208 cm-1
( NH) .
The H1-NMR spectrum of (7a) showed signals (; DMSO-d6) at 4.43(s, 2H,
NCH2), 6.58(s, 1H, olefinic proton), 7.56-8.0(m, 17H, Ar-H) and 9.2-10.2(s,
broad, 2H, 2×NH) disappeared by addition of D2O .
Discussion
83
The mass spectrum of (7b) showed the molecular ion peak [M]+.
m /z = 578
(14.75) .
5. Reaction with 2-amino methyl benzimidazole
It was reported [241] that o-phenylenediamine reacts with glycine in presence of
concentrated hydrochloric acid to give 2-amino methyl benzimidazole (8).
Benzoxazinone (2) react with (8) to give 3-N-substituted quinazolone derivative
(9).
NH2
CH2COOH
H2N
NH2
+CH
2NH
2
N
N
H
C -
(8)
+
R R
CH2 -
CH2NH
2
O
O
N
O
N
N-
N
H
C
NN
N
H
C -
(2)(8) (9)
The structure of and (9) was proved from:
1. Analytical data.
2. Infrared spectra showed bands at 1666 cm-1
(CO of acyclic amide), at
1774-1719 cm-1
( CO of cyclic imide), at 3431cm-1
( NH) .
3. The H1-NMR spectrum of (9) showed signals (; DMSO-d6) at 4.43(s,
2H, NCH2), at 6.76(s, 1H, olefinic proton), at 7.05-8.68 (m, 16H, Ar-H),
at 9.08 (s, broad, 1H, NH), at 13.01(s, broad, 1H, NH, exchangeable with
D2O) .
6. Diels-Alder reaction
The Schiff base of 2-styryl pyridine was found to react smoothly as a diene with
a number of dienophilic compounds [222]. Hydroquinazine adducts was formed
by addition of maleic anhydride to the diene-l-styryl-6,7-dimethoxy-3,4-
dihydro-isoquinoline according to the following equation:
Discussion
84
+
CH = CHC6H
5
H3 CO
H3CO
CH3
O
C6H
5
H3 CO
O
N O
O
O
N
O
O
O
In the present work the reaction of dimethyl maleate with N-(2-(4-
chlorophenyl)-1-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)vinyl)-2-(1,3-
dioxoisoindolin-2-yl)acetamide (2) was investigated.
Thus (2) reacted with dimethyl maleate in dry xylene to give the corresponding
Diels-Alder adducts (10).
C-NHCOCH2-
NHCOCH2-
C6H
4Cl (P-)MeO
2C
MeO2C
CHC6H
4Cl(p-)
O
O
COOCH3
COOCH3
O
O
O
N
O
N
O
O
N
N
(10)
The structure of (10) was established from:
1. Correct analytical data.
Discussion
85
2. Infrared spectra which showed bands at 1642 cm-1
of ( CO of amide), at
1774-1760 cm-1
of ( CO of imide), at 1731 cm-1
( CO of ester), at 1720
cm-1
( CO of sat. benzoxazinone ring), and at 3446 cm-1
( NH).
3. The H1-NMR spectrum of (10) showed signals (; DMSO-d6) at 2.5(s,
6H, COOH3), at 4.1(m, 3H, cyclic protons), at 4.50(s, 2H, NCH2), at 7.35-
8.85(m, 12H, Ar-H), 9.2-10.2(s, broad, 2H, 2NH) disappeared by addition
of D2O .
7. Synthesis of quinazolinyl urea
When benzoxazinone (2) was allowed to react with semicarbazide hydrochloride
in boiling pyridine afforded quinazolinyl urea derivative (11).
Infrared spectrum of (11) showed bands at 1615 cm-1
of ( CO of amides), at
1774-1722 cm-1
of ( CO of cyclic imide) and at 3424cm-1
( NH) .
The H1-NMR spectrum of (11) showed signals (; DMSO-d6) at 4.43 (s, 2H,
NCH2), at 5.8(s, broad, 2H, NH2), at 6.8 (s, 1H, olefinic proton), at 7.5-8.0(m,
12H, Ar-H) and 9.8-10.9(s, broad, 2H, 2×NH) disappeared by addition of D2O.
On fusion of the above compound at its melting point it was cyclized to produce
triazole quinazoline derivative of (12) which shows the bands in IR-spectrum at
1658 cm-1
of ( CO of cyclic and acyclic amides), at 1774-1725 cm-1
of ( CO of
cyclic imide) and at 3468cm-1
( NH).
The H1-NMR spectrum of (12) showed signals (; DMSO-d6) at 4.43 (s, 2H,
NCH2), at 6.74 (s, 1H, olefinic proton), at 7.87-8.0(m, 12H, Ar-H) and 9.6-
10.4(s, broad, 2H, 2×NH) disappeared by addition of D2O .
8. Synthesis of triazino quinazolinone derivative
When benzoxazinone (2) was treated with thiosemicarbazide in boiling pyridine
afforded N-(2-(4-chlorophenyl)-1-(2-thioxo-2,3-dihydro-[1,2,4]triazolo[1,5-
c]quinazolin-5-yl)vinyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide (13).
Discussion
86
Infrared spectrum of (13) showed bands at 1309 of ( CS of cyclic thio amide),
at 1610cm-1
of ( COofα,β- unsaturated amide), at 1774-1719cm-1
of ( CO of
cyclic imide) and at 3462cm-1
( NH) .
The mass spectrum of (13) showed the molecular ion peak [M-3]+.
at m/z = 537
( chart 3).
Table 3 The mass spectrum fragmentation of compound (13)
m/z abundance
537.40 0.09
352 0.25
354 0.18
293 0.31
295 0.27
188 31.17
160 100.00
153 1.24
151 1.78
142 0.36
138 2.44
116 1.80
113 2.51
111 7.34
76 46.79
Discussion
87
Chart 3
Discussion
88
9. Ammonolysis
It was reported[104] that 3,l-(4H)-benzoxazinone derivatives underwent ring
fission with ammonia furnished from ammonium acetate or urea in alcohol to
give N-(substituted) anthranilic acid amide, while by fusion in oil bath or in the
presence of anhydrous zinc chloride the corresponding 2-(substituted)-4-
quinazolones were obtained.
NH3
alcohol
fusionNH3
O = C NH2
O
R
O
N
O
O
O
R
O
N
O
HN
O
R
O
CONH
The present investigation deals with ammonolysis of (2) with ammonia
furnished from ammonium acetate by fusion at 170°C to give the corresponding
2-substituted-4(3H)-quinazol-4-one derivative (14).
R RN
O
O
N
O
NH
(2) (14)
ammoniun acetate
The reaction possibly takes place via ammonolysis followed by cyclization
according to the following mechanism:
Discussion
89
-
H, +H
R
-
NH3
+
NH2
N = C - R
R
NH3
R
R
-H2O
N
O
O O
N
O
C
OH
O
N
NH
O
N
N
OH
(14)
(14')
The structure of (14) was established from:
1. Correct analytical data.
2. Infrared spectrum of (14) showed bands at 1624 cm-1
( CO of α,β-
unsaturated amide), at 1774-1718 cm-1
( CO of cyclic imide) and at
3470, 3362 cm-1
( NH) .
3. The H1-NMR spectrum of (14) (; DMSO-d6) showed signals at 4.42(s,
2H, NCH2), at 6.51 (s, 1H, olefinic proton), at 7.86-8.0(m, 12H, Ar-H),
9.7-10.5(s, broad, 2H, 2NH) disappeared by addition of D2O .
9.1 Chemical proven of compound (14)
The lactam-lactim tautomerism of (14) was further demonstrated chemically by
the following:
9.1.1 Acylation of (14)
While treatment of (14) with phenylisocyanates in presence of anhydrous
potassium carbonate and dry acetone gave 4-substituted-2-substituted
quinazolin-4-ones (15).
Discussion
91
R
N
R
O - CONHPh
Ph-N=C=O
AcetoneN
O
N
NH
(14) (15)
The structure of (15) was proved from the following:
1. The infrared spectrum of (15) showed bands at 1670-1645 cm-1
( CO of
acyclic amide), at 1731cm-1
( CO of carbamate ester), 1774-1740 cm-1
(
CO of cyclic imide) and at 3360-3170 cm-1
(NH).
2. The H1-NMR spectrum of (15) (; DMSO-d6) showed signals at 4.44 (s,
2H, NCH2), 6.94 (s, 1H, olefinic proton), 7.2-8.7(m, 17H, Ar-H), 9.8-
10.95(s, broad, 2H, 2×NH) disappeared by addition of D2O .
9.1.2 Acetylation of quinazol-4-one (14)
Treatment of N-(2 -(4-chlorophenyl) -1-(4-oxo- 3, 4-dihydroquinazolin- 2-
yl)vinyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide (14) with acetic anhydride
afforded N- (1- (3- acetyl- 4- oxo -3, 4- dihydroquinazolin -2- yl) -2- (4-
chlorophenyl) vinyl)-2- (1,3- dioxoisoindolin-2 -yl) acetamide (16).
R
N - COCH3
O
R
Ac2O
N
O
N
NH
(14)(16)
The structure of (16) was established from the following:
1. The infrared spectrum of (16) showed bands at 1617 cm-1
( COofα,β-
unsaturated amide), at 1774-1718 cm-1
( CO of cyclic imide) and at
3474, 3370 cm-1
(NH) .
2. The H1-NMR spectrum of (16) (; DMSO-d6) showed signals at 2.49(s,
3H, COCH3), at 4.42(s, 2H, NCH2), at 6.76 (s, 1H, olefinic proton), at
7.87-8.0(m, 12H, Ar-H) and 9.65-10.5(s, broad, 1H, 1NH) disappeared by
addition of D2O .
Discussion
91
9.1.3 Action of phosphorus pentachloride - phosphorus oxychloride on
quinazol-4-one (14)
The reaction of (14) with a mixture of phosphorus pentachloride and phosphorus
oxychloride gave N-(2-(4-chlorophenyl)-1-(4-chloroquinazolin-2-yl)vinyl)-2-
(1,3-dioxoisoindolin-2-yl)acetamide (17).
R
N
R
POCI3 / PCI
5
CI
N
O
N
NH
(14) (17)
The structure of (17) was established from the following:
1. Correct analytical data.
2. The infrared spectrum showed bands at 1618 cm-1
( CO of α,β-
unsaturated amide), at 1774-1715cm-1
(due to coupling carbonyl bands of
cyclic imide) and at 3470 cm-1
(NH) .
3. The H1-NMR spectrum of (17) (; DMSO-d6) showed signals at 4.44(s,
2H, NCH2), at 6.74 (s, 1H, olefinic proton), at 7.2-8.0(m, 12H, Ar-H) and
at 9.9-10.7(s, broad, 1H, NH) disappeared by addition of D2O .
10. Mannish reaction
Alcoholic solution of 2-substituted quinazol-4-one (14) was condensed with
formaldehyde in the presence imides namely, phthalimide to give the
corresponding Mannish bases 3N-(substituted) quinazol-4-ones (18).
The Mannich intermediate may be formed as follows, taking phthalimide as an
example:
Discussion
92
O
+ HCHO
O
H+
+
+ N = CH2
+ +N - CH
2
O
O
NH
O
N
O
N-CH2-
2
O
O
NH
O
O
O
O
H2O
The reaction possibly takes place according to the following mechanism:
+
R
N
R
OH
H2C = NN
N - CH2 - N
R
OH+
N
O
O
O
N
NH
N O
O
N
Discussion
93
N - CH2 - NH
R
+ base
N - CH2 - N
R
BH
+
+
O
O
N
O
H B;
O
O
N
O
N
(18)
The structure of (18) was proved from:
1. Analytical data
2. The infrared spectrum showed bands at 1613 cm-1
( COofα,β- unsaturated
amide), at 1774-1721cm-1
( CO of cyclic imides) and at 3432 cm-1
(NH) .
3. The H1-NMR spectrum of (18) (; DMSO-d6) showed signals at 4.09 (s, 2H,
CH2), at 4.42(s, 2H, NCH2), at 5.82 (s, 1H, olefinic proton), at 7.91-7.93(m,
16H, Ar-H) and at 9.9-10.7(s, broad, 1H, NH) disappeared by addition of
D2O .
11. Synthesis of ethyl 2-(2-(2-(4-chlorophenyl)-1-(2-(1,3-
dioxoisoindolin-2-yl)acetamido)vinyl)quinazolin-4-yloxy)acetate
Quinazolinone (14) reacts with ethyl chloroacetate in dry acetone and in the
presence of dry potassium carbonate to give compound (19).
The structure of (19) was established from:
1. Correct analytical data.
2. The infrared spectrum showed bands at 1660 cm-1
( CO of acyclic
amide), at 1774- 1719 cm-1
( CO of cyclic imide), 1731cm-1
( CO of
ester) and at 3440, 3328 cm-1
(NH).
3. The H1-NMR spectrum of (19) (; DMSO-d6) showed band at 1.1-2.5
(m, with interference, 5H, COOCH2CH3), at 4.43 (s, 2H, NCH2), at
4.83(s, 2H,OCH2COO), at 6.63(s, 1H, olefinic proton), at 7.86-7.95 (m,
Discussion
94
12H, Ar-H) and 9.5-10.2 (s, broad, 1H, NH) disappeared by addition of
D2O .
11.1 Chemical proven of compound (19)
From hydrazinolysis of the ester by hydrazine hydrate to yield the
hydrazide derivative (20).
The structure of (20) was established from:
1. Correct analytical data.
2. The infrared spectrum showed bands at 1623 cm-1
( CO of α,β-
unsaturated amide) , at 1774-1719 cm-1
( CO of cyclic imide) and at
3426 cm-1
(NH) .
3. The H1-NMR spectrum of (20) (; DMSO-d6) showed signals at 4.76
(s, 2H, NCH2), at 4.82(s, 2H, OCH2CO), at 6.72 (s, 1H, olefinic
proton), 7.84-8.1(m, 12H, Ar-H), 9.65-10.5(s, broad, 2H, 2×NH)
disappeared by addition of D2O .
12. Action of phenyl isocyanate on quinazolinone (20)
Quinazolinone (20) reacts with phenyl isocyanate in dioxane to give 2-(2-(2-(2-
(4-chlorophenyl)-1-(2-(1,3-dioxoisoindolin-2-yl)acetamido)vinyl)quinazolin-4-
yloxy)acetyl)-N-phenylhydrazinecarboxamide (21).
The structure of (21) was established from:
1. Correct analytical data.
2. The infrared spectrum showed bands at 1615cm-1
( CO of α,β-
unsaturated amide), at 1774-1719 cm-1
( CO of cyclic imide) and at 3366
cm-1
(NH) .
3. The H1-NMR spectrum of (21) (; DMSO-d6) showed signals at 4.43(s,
2H, NCH2), at 6.51 (s, 1H, olefinic proton), at 7.85-8.1(m, 12H, Ar-H),
9.65-10.5(s, broad, 4H, 4×NH) disappeared by addition of D2O .
Discussion
95
13. Action of p-chlorobenzaldhyde on quinazolinone (20)
Quinazolinone (20) reacts with p-chlorobenzaldhyde in absolute ethanol
and 1ml pipridine to give (22).
The structure of (22) was established from:
1. Correct analytical data.
2. The infrared spectrum showed bands at 1615 cm-1
( CO of α,β-
unsaturated amide), at 1774-1722 cm-1
( CO of cyclic imide) and at 3424
cm-1
(NH) .
3. The H1-NMR spectrum of (22) (; DMSO-d6) showed signals at 4.6(s,
2H, NCH2), at 6.6 (s, 1H, olefinic proton), at 6.74 (s, 1H, N=CH), at 7.74-
8.09(m, 16H, Ar-H) and at 9.6-10.2(s, broad, 2H, 2×NH) disappeared by
addition of D2O .
14. Base catalysed reaction with hydroxylamine hydrochloride
Recently, [103] it was reported that 2-substitutedbenzoxazinones reacted with
hydroxylamine hydrochloride in refluxing pyridine to give 2-substituted 3-
hydroxy-4-quinazolone.
O
O
R
O
N - OH
R
NH2OH.HCI
pyridineN N
In pursuit the above result, the author investigated the reaction of hydroxylamine
hydrochloride with N-(2-(4-chlorophenyl)-1-(4-oxo-4H-benzo[d][1,3]oxazin-2-
yl)vinyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide (2) in the presence of sodium
acetate in boiling ethanol to give N-(2-(4-chlorophenyl)-1-(3-hydroxy-4-oxo-
3,4-dihydroquinazolin-2-yl)vinyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide.
O
O
R
O
N - OH
R
H2NOH.HCI
alcohol / AcONaN N
(2) (23)
Discussion
96
The formation of (23) possibly takes place according to the following
mechanism:
O
R
O
R
NH2OH.HCI
NH2OH
+
- +
R
NH2OH-
O
base
H
NH - OH
+
-H
..
O
RNH-OH
HO
R
+
-
-H NH
HOH
R
-H2O
O
N-OH
R
N
O
N
O
N
O
N
C
O
+H
C
N
O
+HN
O
N
The structure of (23) was established from:
1. Correct analytical data.
2. Infrared spectrum for (23) showed bands at 1617 cm-1
( CO of cyclic and
a cyclic amide), at 1774-1720 cm-1
( CO of cyclic imide), and at 3848,
3743, 3485 cm-1
(OH and NH) .
3. The H1-NMR spectrum of (23) (; DMSO-d6) showed signals at 4.43(s,
2H, NCH2), at 6.75 (s, 1H, olefinic proton), 7.3-7.95(m, 12H, Ar-H), at
8.68 (s, broad, 1H, NH) and at 10.69(s, 1H, OH) .
14.1 Chemical proven of compound (23)
14.1.1 Acetylation of 3-N-hydroxy-4-quinazolone
The acylation of the readily available (23) investigated thus, treatment of (23)
with excess of acetic anhydride gave 2-(2-(4-chlorophenyl)-1-(2-(1,3-
dioxoisoindolin-2-yl)acetamido)vinyl)-4-oxoquinazolin-3(4H)-yl acetate (24).
N - O - C - CH3
R
(CH3CO)
2ON-OH
R N
O O
N
O
(23) (24)
The structure of (24) was established from:
1. Correct analytical data.
2. Infrared spectrum for (24) showed bands at 1660 cm-1
( CO of cyclic and
acyclic amide), at 1774-1720 cm-1
( CO of cyclic imide), 1731cm-1
(
CO of ester), and at 3462, 3328 cm-1
(NH).
Discussion
97
3. The H1-NMR spectrum of (24) (; DMSO-d6) showed signals at 2.49 (s,
3H, OCOCH3), 4.42(s, 2H, NCH2), at 6.75 (s, 1H, olefinic proton), 7.87-
7.95(m, 12H, Ar-H) and at 9.6-10.2(s, broad, 1H, NH) disappeared by
addition of D2O .
14.1.2 Reaction with ethyl chloroacetate
Another reaction which confirm the presence of hydroxyl group is the reaction
with ethyl chloroacetate in dry acetone which leads to formation of ethyl 2-(2-
(2-(4-chlorophenyl)-1-(2-(1,3-dioxoisoindolin-2-yl)acetamido)vinyl)-4-
oxoquinazolin-3(4H)-yloxy)acetate (25).
1. The structure of compound (25) were supported by their infrared spectrum
which showed bands at 1660 cm-1
( CO of cyclic and acyclic amide), at
1774-1722 cm-1
( CO of cyclic imide), 1732 cm-1
( CO of ester) and at
3440, 3324 cm-1
(NH).
2. The H1-NMR spectrum of (25) (; DMSO-d6) showed signals at 1.2(t,
3H, CH3), at 4.1(q, 2H, CH2 of ester), at 4.42 (s, 2H, NCH2), at 4.83(s,
2H,OCH2COO), at 6.63(s, 1H, olefinic proton), at 7.4-7.9 (m, 12H, Ar-H)
and 9.5-10.2 (s, broad, 1H, NH) disappeared by addition of D2O .
14.1.2.1 Chemical proven of compound (25)
From hydrazinolysis of the ester by hydrazine hydrate to yield the hydrazide
derivative (26).
The structure of (26) was established from:
1. Correct analytical data.
2. The infrared spectrum showed bands at 1680-1660 cm-1
( CO of amides
and hydrazide), at 1774-1723 cm-1
( CO of cyclic imide) and at 3480-
3220 cm-1
(NH and NH2).
3. The H1-NMR spectrum of (26) (; DMSO-d6) showed signals at 4.42(s,
2H, NCH2), at 4.82(s, 2H, OCH2CO), at 6.6(s, 1H, olefinic proton), 7.09-
8.06(m, 12H, Ar-H), 9.65-10.5(s, broad, 2H, 2×NH) disappeared by
addition of D2O .
Discussion
98
15. Action of phenyl isocyanate on quinazolinone (26)
Quinazolinone (26) reacts with phenyl isocyanate in dioxane to give 2-(2-(2-(2-
(4-chlorophenyl)-1-(2-(1,3-dioxoisoindolin-2-yl)acetamido)vinyl)quinazolin-4-
yloxy)acetyl)-N-phenylhydrazinecarboxamide (27).
The structure of (27) was established from:
1. Correct analytical data.
2. The infrared spectrum showed bands at 1662 cm-1
( CO of amides), at
1774-1718 cm-1
( CO of cyclic imide), and at 3462, 3320 cm-1
(NH).
3. The H1-NMR spectrum of (27) (; DMSO-d6) showed signals at 4.43(s,
2H, NCH2), at 5.82 (s, 1H, olefinic proton), at 7.85-8.08 (m, 12H, Ar-H),
9.65-10.5(s, broad, 4H, 4×NH) disappeared by addition of D2O .
16. Action of p-chlorobenzaldhyde on quinazolinone (26)
Quinazolinone (26) reacts with p-chlorobenzaldhyde in absolute ethanol
and 1ml pipridine to give (28).
The structure of (28) was established from:
1. Correct analytical data.
2. The infrared spectrum showed bands at 1666 cm-1
( CO of amides), at
1774-1716 cm-1
( CO of cyclic imide) and at 3445 cm-1
(NH).
3. The H1-NMR spectrum of (28) (; DMSO-d6) showed signals at 4.43 (s,
2H, NCH2), at 6.5 (s, 1H, olefinic proton), at 6.7 (s, 1H, N=CH), at 7.78-
8.09 (m, 16H, Ar-H) and at 9.6-10.2(s, broad, 2H, 2×NH) disappeared by
addition of D2O .
BILOGICAL ACTIVITY
Studies on 4H-3,1-Benzoxazin-4-ones
Bilogical Activity
111
BILOGICAL ACTIVITY
The behavior of the synthesized organic compounds as antibacterial was
investigated at the Micro analytical unit, Cairo University, Egypt.
The antimicrobial activity of synthesized derivatives was examined in vitro by
hole plate and filter paper disc methods. Some compounds were tested for
activity Gram-positive, Gram-negative bacteria and fungi using tetracycline and
amphotericin B as a reference standard.
The results show the effectively of compounds 2, 4a, 5, 7a, 14 and 23 against
bacteria, Escherichia Coli(G-) (cf. Fig.1,2,3), Staphylococcus Aureus (G
+) (cf.
Fig. 4,5,6) and Candida albicans (fungus) (cf. Fig.10,11,12) and the
ineffectively against Aspergillus Flavus (fungus) (cf. Fig.7,8,9)
On the other hand, for compounds 3b, 3f and 15 the results show its effective
against bacteria, Es (cf. Fig. 1, 3), and St (cf. Fig.4, 6), and its ineffective against
fungi As (cf. Fig.7,9), and Ca (cf. Fig. 10, 12).
Moreover, the results show the effectively of compounds 9, 10, 11, 12, 14, 17,
18, 19, 20, 22, 25, 27and 28 against bacteria, Escherichia Coli(G-),
Staphylococcus Aureus (G+) and Candida albicans (fungus) and the
ineffectively against Aspergillus Flavus (fungus).
For compounds 6, 16, 21, 24 and 26 the results show its effective against
bacteria, Es and St and its ineffective against fungi As and Ca. The results are
summarized in (Table 4).
Es: Escherichia Coli
St: Staphylococcus Aureus
As: Aspergillus Flavus
Ca: Candida albicans
Bilogical Activity
111
Table 4 Relative activity of the some compounds against (G+),(G-) bacteria
and fungi
Sample Inhibition zone diameter (mm/mg sample)
Escherichia
Coli (G-)
Staphylococcus
Aureus(G+)
Aspergillus
Flavus (Fungus)
Candida
albicans (Fungus)
Control : DMSO 0.0 0.0 0.0 0.0
Stan
dar
d
Tetracycline
Antibacterial agent
34 32 -- --
Amphotericin B
Antifungal agent
-- -- 18 20
2 15 15 0.0 12
3b 15 16 0.0 0.0
3f 14 14 0.0 0.0
4a 12 13 0.0 10
5 14 13 0.0 13
6 12 13 0.0 0.0
7a 11 10 0.0 10
9 12 13 0.0 10
10 14 13 0.0 13
11 11 10 0.0 10
Bilogical Activity
112
Sample Inhibition zone diameter (mm/mg sample)
Escherichia
Coli (G-)
Staphylococcus
Aureus(G+)
Aspergillus
Flavus (Fungus)
Candida
albicans (Fungus)
Control : DMSO 0.0 0.0 0.0 0.0
Stan
dar
d
Tetracycline
Antibacterial agent
34 32 -- --
Amphotericin B
Antifungal agent
-- -- 18 20
12 15 15 0.0 12
13 15 16 0.0 0.0
14 13 14 0.0 12
15 11 10 0.0 0.0
16 15 16 0.0 0.0
17 14 13 0.0 12
18 13 12 0.0 10
19 12 13 0.0 10
20 14 13 0.0 13
21 12 10 0.0 0.0
22 15 16 0.0 10
Bilogical Activity
113
Sample Inhibition zone diameter (mm/mg sample)
Escherichia
Coli (G-)
Staphylococcus
Aureus(G+)
Aspergillus
Flavus (Fungus)
Candida
albicans (Fungus)
Control : DMSO 0.0 0.0 0.0 0.0
Stan
dar
d
Tetracycline
Antibacterial agent
34 32 -- --
Amphotericin B
Antifungal agent
-- -- 18 20
23 15 15 0.0 12
24 15 16 0.0 0.0
25 13 14 0.0 12
26 11 10 0.0 0.0
27 14 13 0.0 13
28 11 10 0.0 10
FIGURES
Studies on 4H-3,1-Benzoxazin-4-ones
115
BIOLOGICAL ACTIVITY
Escherichia coli (G-)
Figure 1
Figure 2
Figure 3
116
Staphylococcus aureus (G+)
Figure 4
Figure 5
Figure 6
117
Aspergillus flavus(fungus)
Figure 7
Figure 8
Figure 9
118
Candida albicans (fungus)
Figure 10
Figure 11
Figure 12
EXPERMINTAL
Studies on 4H-3,1-Benzoxazin-4-ones
Experimental
111
EXPERMINTAL
Melting points were measured on electrothermalmelting point apparatusand are
uncorrected. IR model 550 spectrophotometers. Mass spectra were recorded at
70 ev with a varian MAT 311. 1H-NMR spectra were determined on
BruckerWpsy 200 MHz spectrometer with TMS as internal standard. The
chemical shifts are in ppm. Solvent was DMSO. All analysis was carried out at
MicroAnalyticalCenter, Faculty of Science, Cairo University, Egypt. The
chemicals and reagents were purchased from EL- Gomhouria Company, Egypt.
Physical data and analytical data for the synthesized compounds have been
summarized in (Table 5, 6).
1. Synthesis and reactions of N-(2-(4-chlorophenyl)-1-(4-oxo-
4H-benzo[d][1,3]oxazin-2-yl)vinyl)-2-(1,3-dioxoisoindolin-2-
yl)acetamide (2)
A mixture of (Z)-2-((4-(4-chlorobenzylidene)-5-oxo-4,5-dihydrooxazol-2-
yl)methyl)isoindoline-1,3-dione (1) (0.05 mol) and anthranilic acid (0.035 mol)
in boiling n-butanol was heated under reflux for 10 hrs.The solid product
obtained was crystallised from benzene to give compound (2) .
2. Action of primary amines on (2): formation of (3a-h)
A solution of (2) (0.01 mol) and primary amines, namely methylamine,
ethylamine, butyl amine, pentylamine, hexyl amine,glycine, p-anisidine and o-
phenylenediamine(0.01 mol) in (50 ml) ethanol was refluxed for 4 hrs. The solid
product was separated on cooling and crystallized from the proper solvent to
give (3a-h).
3. Action of hydrazines on (2): Formation of (4a,b)
A solution of benzoxazinone (2) (0.01mol) with hydrazine hydrate (0.02mol) in
ethanol (30 ml) was refluxed for 4 hrs, the product that separated on cooling was
crystallized from the pet.ether(40-60) to give the hydrazide derivative (4a).
On the other hand, reaction of (2) (0.01 mol) with phenyl hydrazine (0.02 mol)
in ethanol (30 ml) was refluxed for 4 hrs. The product that separated on cooling
was crystallized from benzene to give quinazolinone derivative (4b).
4. Action of active methylene on benzoxazinone (2): Formation of
1,4-quinolinone (5)
A solution of (2) (0.01 mol) and ethyl acetoacetate (0.03 mol) in pyridine (50
ml) was refluxed for 4 hrs. The reaction mixture was cooled and poured into ice
/ HCl. The separated product was filtered off and crystallized from ethanol to
give (5).
Experimental
111
5. Action of sodium azide on benzoxazinone (2): Formation of
tetrazole (6)
A mixture of benzoxazinone (2) (0.01 mol) and sodium azide (0.05 mol) in
boiling acetic acid (50 ml) was refluxed for 3 hrs. The separated product
obtained after concentration was crystallized from ethanol to give tetrazole
derivative (6).
6. Action of aromatic substrates on benzoxazinone (2) in presence
of anhydrous AlCl3: Formation of o-aroylanilides (7a,b)
Anhydrous AlCl3 (0.03 mol) was added under stirring to (2) (0.01 mol) in dry
aromatic substrate namely benzene and toluene at room temperature. The
reaction mixture was stirred for 3 hrs, and the resultant complex formed
decomposed with ice/dilHCl. The solvent was steam distilled and the residual
solid filtered and crystallized from the proper solvent to give (7a,b).
7. 2-Amino methyl benzimidazole (8)
A mixture of the equimolar amounts of o-phenylenediamine and glycine was
heated for 2.5 hrs under reflux in the presence of conc. HCl subsequently
reaction mixture was concentrated and the desired product separated out on
cooling crystallized, from ethanol to give (8).
8. Action of (8) on benzoxazinone (2): Formation of 2-
substdituted- 3-methyl-[2'-benzimidazolyl]-( 4H)- 3,1-quinazolin-
4-one (9)
A mixture of 2-Amino methyl benzimidazole (8) (0.01 mol) and benzoxazin-4-
one (2) (0.01 mol) in (30 ml) dry pyridine was refluxed for 6 hrs. The reaction
mixture was poured into ice/HCl. The solid product that separated out was
washed repeated with water and crystallized from ethanol to give (9).
9. Diels-Alder reaction on (2):
A mixture of benzoxazinone (2) (0.01 mol) and dimethyl maleate (0.01 mol) in
dry xylene (50 ml) was refluxed for 20 hrs. The reaction mixture was filtered
upon hot, the filtration was concentrated and cooled. The separated product
obtained was crystallized from benzene to give (10).
10. Synthesis of quinazolinylurea (11)
A solution of benzoxazinone (2) (0.01mol) in (40 ml) pyridine with
semicarbazide hydrochloride (0.01mol) was refluxed for 6hrs, left to cool ,
poured into cold water with stirring ,the solid that separated out was filtered off ,
washed with cold water, dried and crystallized from ethanol to give (11).
Experimental
112
11. Cyclization of quinazolinylurea(12)
On fusion of quinazolinylurea derivative for 2 hrs on sand bath above melting
point. The solid product after cooling was crystallized from pet-ether(40-60) to
give (12).
12. Action of thiosemicarbazide on benzoxazone (2)
A mixture of benzoxazinone (2) (0.01 mol) and thiosemicarbazide (0.01 mol) in
dry pyridine (30 ml) was refluxed for 4 hrs, left to cool , poured into ice/HCl,
filtered off and crystallized from methanol to give (13).
13. Action of ammonium acetate or formamide on (2):Formation
of quinazolone (14)
(0.01 mol) of benzoxazinone (2) was fused with (0.02 mol) ammonium acetate
on sand bath above the melting point for 3hrs. The reaction mixture after cooling
was poured into water, filtered off and crystallized from benzene to give (14).
14. Acylation of (14): Formation of (15)
A mixture of (14) (0.01 mol) , anhydrous potassium carbonate (0.04mol) and
phenyl isocyanate (0.042 mol) was heated for 24 hrs under reflux in (50 ml) dry
acetone. The reaction mixture after removing the excess solvent was poured into
cold water, the solid that separated out was filtered off, dried and crystallized
from ethanol solvent to give (15).
15. Action of acetic anhydride on (14): Formation of 3N-acetyl
quinazolone (16)
Treatment of (14) with excess acetic anhydride (20 ml) was refluxed for 3 hrs.
After cooling the product obtained was washed with water; filtered off, dried
and crystallized from ethanol to give (16).
16. Action of phosphorus pentachloride - phosphorus oxychloride
on quinazol-4-one (14)
(0.01 mol) quinazolinone (14) and a mixture of PCl5 (0.01 mol), POCl3 (2 ml)
was heated in water bath for 5 hrs. After cooling the reaction mixture was
poured into ice , filtered offand crystallized from benzene to give (17).
17. Mannish reaction on quinazolone (14): Formation of Mannish
bases (18)
A mixture of (14) (0.01 mol), formaldehyde (5 ml) and phthalimide (0.01mol) in
boiling aceticacid and (30 ml) was refluxed for 4hrs, after cooling the separated
product was crystallized from ethanol to give Mannish base (18).
Experimental
113
18. Action of ethyl chloroacetate on quinazolinone (14)
A mixture of (14) (0.01mol) , anhydrous potassium carbonate (0.04mol) and
ethyl chloroacetate (0.04mol) in (60 ml) dry acetone was refluxed for 24hrs.The
product obtained after removing the excess solvent was poured into cold
water,the solid that separated out was filtered off , dried and crystallized from
methanol to give (19).
19. Action of hydrazine hydrate on quinazolinone (19)
A mixture of (19) (0.01mol) and hydrazine hydrate (0.01mol) in (40 ml) ethanol
was refluxed for 3hrs,after cooling ,the solid that separated out was filtered off ,
dried and crystallized from dioxane to give (20).
20. Action of phenyl isocyanate on quinazolinone (20)
An equimolecular quantity of amino carbmoyl derivative (20) (0.01mol) and
phenyl isocyanate (0.01mol) in dioxane (40 ml) was refluxed for 6hrs. On
cooling at room temperature, the fine crystals which was appeared, filtered off
and dried and crystallized from ethanol to give (21).
21. Action of aldehyde on quinazolinone (20)
A mixture of (20) (0.01mol) and p-chlorobezaldehyde (0.012mol) in (50 ml)
ethanol containing (1ml) pipridine was refluxed for 3hrs, after cooling,the solid
that separated out was filtered off , dried and crystallized from ethanol to give
(22).
22. Action of hydroxylamine hydrochloride on benzoxazone (2)
Formation of 3-hydroxy-4-quinazolone (23)
A mixture of (2) (0.01 mol), hydroxylamine hydrochloride (0.03 mol) and
sodium acetate (0.03 mol) in ethyl alcohol (50 mol) was heated under reflux for
5 hrs. The reaction mixture after cooling was poured into water, filtered off and
crystallized from benzene to give (23).
23. Action of acetic anhydride 3-hydroxy quinazolone (23)
Formation of (24)
Treatment of (23) (0.01 mol) with excess of acetic anhydride (25 ml) was
refluxed for 2 hrs. After cooling the solid product obtained was washed with
water, filtered off, dried and crystallized from benzene to give (24).
24. Action of ethyl chloroacetate on 3-hydroxy-4-quinazolone (23)
A mixture of (23) (0.01mol), anhydrous potassium carbonate (0.04mol) and
ethyl chloroacetate (0.04mol) in (60 ml) dry acetone was refluxed for 24hrs.The
product obtained after removing the excess solvent was poured into cold
Experimental
114
water,the solid that separated out was filtered off , dried and crystallized from
ethanol to give ( 25).
25. Action of hydrazine hydrate on quinazolinone (25)
A mixture of (25) (0.01mol) and hydrazine hydrate (0.01mol) in (40 ml) ethanol
was refluxed for 3hrs, after cooling,the solid that separated out was filtered off ,
dried and crystallized from dioxane to give (26).
26. Action of phenyl isocyanate on quinazolinone (26)
An equimolecular quantity of amino carbmoyl derivative (26) (0.01mol) and
phenyl isocyanate (0.01mol) in dioxane (40 ml) was refluxed for 6hrs. On
cooling at room temperature, the fine crystals which was appeared, filtered off,
dried and crystallized from ethanol to give (27).
27. Action of aldehyde on quinazolinone (26)
A mixture of (26) (0.01mol) and p-chlorobezaldehyde (0.012mol) in (50 ml)
ethanol containing (1ml) pipridine was refluxed for 3hrs,after cooling ,the solid
that separated out was filtered off , dried and crystallized from ethanol to give
(28).
Table 5 Characteristics and Physical Data for the Synthesized Compounds
Com-
pound
Empirical
formula
M.wt Solvent Yield
%
Calculated/ Found, % m.p, 0C C H O N Cl S
2 C26H16ClN3O5 485.88 benzene 72 64.27
64.23
3.32
3.64
16.46
16.49
8.65
8.32
7.30
7.26
- 150-152
3a C27H21ClN4O5 516.93 benzene 76 62.73
62.41
4.09
4.23
15.48
15.63
10.48
10.44
6.86
7.15
- 230-232
3b C28H23ClN4O5 530.96 ethanol
75 63.34
63.07
4.37
4.28
15.07
15.22
10.55
10.05
6.68
6.97
- 218-220
3c C30H27ClN4O5 559 ethanol 65 64.46
64.16
4.87
5.02
14.31
13.99
10.02
10.05
6.34
6.02
- 250-252
3d C31H29ClN4O5 573 ethanol 67 64.97
64.08
5.10
5.39
13.96
13.63
9.78
9.46
6.19
6.22
- 220-222
3e C32H31ClN4O5 587 ethanol 62 65.47
65.5
5.32
4.99
13.63
13.92
9.54
9.58
6.04
6.01
- 270-272
3f C28H21ClN4O7 560.94 ethanol 80 59.95
59.98
3.77
3.45
19.97
20.3
9.99
10.27
6.32
6.06
- 180-182
3g C33H25ClN4O6 609.03 benzene 70 65.08
65.11
4.14
3.71
15.76
16.05
9.20
9.49
5.82
5.47
- 60-62
3h C32H24ClN5O5 594.02 benzene 85 64.70
64.73
4.07
4.39
13.47
13.04
11.79
11.38
5.97
5.94
- 100-102
4a C26H24ClN7O5 549.97 Pet-ether
40-60
70 56.78
56.74
4.40
4.43
14.55
13.22
17.83
17.79
6.45
6.74
- 98-100
Experimental
115
Com-
pound
Empirical
formula M.wt Solvent
Yield
%
Calculated/ Found, % m.p, 0C C H O N Cl S
4b C32H22ClN5O4 576 benzene 75 66.73
66.69
3.85
4.18
11.11
10.79
12.16
11.88
6.16
6.19
- 75-77
5 C30H22ClN3O6 555.97 ethanol 60 64.81
64.53
3.99
3.56
17.27
17.3
7.56
7.88
6.38
5.49
- 240-242
6 C26H17ClN6O5 528.9 ethanol 65 59.04
59.36
3.24
2.96
15.13
15.16
15.89
15.63
6.70
7.02
- 222-224
7a C32H22ClN3O5 563.99 benzene 75 68.15
68.12
3.93
3.61
14.18
13.92
7.45
7.42
6.29
5.96
- 190-192
7b C33H24ClN3O5 578 benzene 78 68.57
68.89
4.19
3.76
13.84
13.56
7.27
7.56
6.13
5.81
- 170-172
8 C8H9N3 147.18 ethanol 65 65.29
65.26
6.16
5.73
- 28.25
28.54
- - 245-247
(lit)
9 C34H23ClN6O4 615.04 ethanol 67 66.40
66.38
3.77
3.45
10.41
10.13
13.66
13.95
5.76
5.79
- 190-192
10 C32H24ClN3O9 630 benzene 50
61.01
60.99
3.84
3.43
22.86
23.19
6.67
6.95
5.63
5.31
- 230-232
11 C27H19ClN6O5 542.93 ethanol 60 59.73
59.41
3.53
3.25
14.73
15.02
15.48
15.81
6.53
6.1
- 60-62
12 C27H17ClN6O4 524.91 Pet-ether
40-60
60 61.78
61.52
3.26
3.22
12.19
12.52
16.01
15.66
6.75
6.78
- 222-224
13 C27H17ClN6O3S 540.98 Methanol 75 59.94
60.26
3.17
3.6
8.87
8.46
15.53
15.27
6.55
6.88
5.93
6.25
190-192
14 C26H17ClN4O4 484.89 benzene 68 64.40
64.08
3.53
3.51
13.20
14.53
11.55
11.23
7.31
7.6
- 218-220
15 C33H22ClN5O5 603.13 ethanol 58 65.62
65.91
3.67
3.99
13.24
12.81
11.59
11.33
5.87
5.9
- 210-212
16 C28H19ClN4O5 526.10 ethanol 62 63.82
63.54
3.63
3.3
15.18
14.92
10.63
10.66
6.73
7.02
- 205-207
17 C26H16Cl2N4O3 503.34 benzene 72 64.04
64.33
3.20
2.79
9.54
9.57
11.13
11.42
14.09
13.74
- 190-192
18 C35H22ClN5O6 643.13 ethanol 55 65.27
64.94
3.44
3.76
14.91
14.5
10.87
11.16
5.50
5.15
- 195-197
19 C30H23ClN4O6 570.98 Methanol
75 63.11
62.85
4.06
3.73
16.81
15.92
9.81
9.84
6.21
6.5
- 165-167
20 C28H21ClN6O5 556.13 Dioxane 65 60.38
60.71
3.80
4.12
14.36
14.39
15.09
14.74
6.37
6.11
- 175-177
21 C35H26ClN7O6 573 ethanol 67 62.18
62.51
3.88
3.56
14.20
14.49
14.50
14.07
5.24
5.27
- 210-212
22 C35H26Cl2N6O5 587 ethanol 62
65.47
65.5
5.32
4.99
13.63
13.92
9.54
9.51
6.04
6.01
- 270-272
23 C26H17ClN4O5 500.89 benzene 62
62.34
62.01
3.42
3.71
15.97
15.94
11.19
11.48
7.08
6.76
- 220-222
24 C28H19ClN4O6 542.10 benzene 63
61.94
61.62
3.53
3.2
17.68
17.97
10.32
10.04
6.53
6.86
- 230-232
Experimental
116
Com-
pound
Empirical
formula M.wt Solvent
Yield
%
Calculated/ Found, % m.p, 0C C H O N Cl S
25 C30H23ClN4O7 586.13 ethanol 58
61.39
61.36
3.95
3.91
19.08
19.06
9.54
9.51
6.04
6.01
- 155-157
26 C28H19ClN4O5 572.96 Dioxane 62
58.70
58.66
3.69
3.67
16.75
16.78
14.67
14.93
6.19
5.84
- 180-182
27 C35H26ClN7O7 692.08 ethanol 55
60.74
61.06
3.79
4.22
16.18
16.44
14.17
14.14
5.12
4.8
- 230-232
28 C26H17ClN4O5 697.52 ethanol 62
60.27
59.98
3.76
3.43
13.76
14.05
12.05
12.08
10.17
9.91
- 260-262
Experimental
117
Table 6 H1-NMR, MS and IR data of prepared compounds
Compd.No. H1-NMR(δinppm) MS
(m/z,%)
IR cm-1
νN-H νC=O
2 4.45(s, 2H, NCH2CO), at
6.75 (s, 1H, olefinic proton),
at 7.22-7.91 (m, 12H, Ar-H)
and at 9.08 (s, 1H, NH)
[M]+.
485.55,
[M+2]+.
487
3475, 3370 1614 cm-1
( CO
ofα,β-
unsaturated
amide), at 477٤-
1720 cm-1
( CO
of benzoxazinone
and CO of
cyclic imide)
3a _ [M]+.
516.45,
[M+2]+.
518.5
3317, 3133 1647 (acyclic
amides)
1774-1713
(cyclic imide)
3b 1.2(t, 3H, CH3), at 4.1(q, 2H,
CH2), at 4.43(s, 2H,
NCH2CO), at 6.74(s, 1H,
olefinic proton), at 7.2-7.92
(m, 12H, Ar-H) and 9.80-
10.38(s, broad, 3H, 3×NH)
disappeared by addition of
D2O
_ 3473, 3220 1645 (acyclic
amides)
1774-1715(cyclic
imide)
3c
_
[M+1]+.
560,
[M+2]+.
561
3465, 3322 1643 (acyclic
amides)
1774-1717(cyclic
imide)
3d _ _ 3475, 3240 1641 (acyclic
amides)
1774-1719(cyclic
imide)
3e _ _ 3448, 3350 1650 (acyclic
amides)
1774-1720(cyclic
imide)
3f _ _ 3360 1640 (acyclic
amides)
1774-1712(cyclic
imide)
3g _ _ 3455, 3360 1644 (acyclic
amides)
1774-1716(cyclic
imide)
3h _ _ 3330, 3310 1640 (acyclic
amides)
1774-1711(cyclic
imide)
Experimental
118
Compd.No. H1-NMR(δinppm)
MS
(m/z,%)
IR cm-1
νN-H νC=O
4a _ [M]+.
549
3445 1617(α,β-
unsaturated
amide) 1774-
1720 (cyclic
imide)
4b _ 3460, 3380 1646 (cyclic
and acyclic
amides) 1774-
1714 (of
cyclic imide)
5 1.2-2.49 (m, with
interference, 5H,
COOCH2CH3), at 4.42 (s,
2H, NCH2), at 3.37(s,
2H,CH2), at 6.74(s, 1H,
olefinic proton), at 7.89-7.91
(m, 12H, Ar-H) and 9.5-10.2
(s, broad, 1H, NH)
disappeared by addition of
D2O
_ 3479 1611(α,β-
unsaturated
amide) 1725
(ester)
1774 (imide)
6 4.55(s, 2H, NCH2CO), at
6.85 (s, 1H, olefinic proton),
at 7.25-8.20 (m, 12H, Ar-H)
and at 9.98-10.69(s, broad,
1H, NH) and at 13.84 (s, 1H,
OH)
_ 3455-2928
For OH and NH
1614(α,β-
unsaturated
amide) 1718
( CO of
carboxylic)
1774-1760
(due to
coupling
carbonyl
bands of
cyclic imide)
7a 4.43(s, 2H, NCH2), 6.58(s,
1H, olefinic proton), 7.56-
8.0(m, 17H, Ar-H) and 9.2-
10.2(s, broad, 2H, 2×NH)
disappeared by addition of
D2O
_ 3401,3208 1657cm-1
(,-
unsaturated
amide) 1774-
1725 (cyclic
imide)
7b _ [M]+.
578 3401,3208 1657cm-1
(,-
unsaturated
amide) 1774-
1725 (cyclic
imide)
9 4.43(s, 2H, NCH2), at 6.76(s,
1H, olefinic proton), at 7.05-
8.68 (m, 16H, Ar-H), at 9.08
(s, broad, 1H, NH), at
13.01(s, broad, 1H, NH,
exchangeable with D2O)
_ 3431 1666 (acyclic
amide)
1774-1719
(cyclic imide)
Experimental
119
Compd.No. H1-NMR(δinppm)
MS
(m/z,%)
IR cm-1
νN-H νC=O
10 2.5(s, 6H, COOH3), at 4.1(m,
3H, cyclic protons), at 4.50(s,
2H, NCH2), at 7.35-8.85(m,
12H, Ar-H), 9.2-10.2(s, broad,
2H, 2NH) disappeared by
addition of D2O
_ 3446 1642 (amide)
1774-1740
(imide)
1731 (ester)
1720 (sat.
benzoxazinone
ring)
11 4.43 (s, 2H, NCH2), at 5.8(s,
broad, 2H, NH2), at 6.8 (s, 1H,
olefinic proton), at 7.5-8.0(m,
12H, Ar-H) and 9.8-10.9(s,
broad, 2H, 2×NH) disappeared
by addition of D2O
_ 3424 1615 (amides)
1774-1722
(cyclic imide)
12 4.43 (s, 2H, NCH2), at 6.74 (s,
1H, olefinic proton), at 7.87-
8.0(m, 12H, Ar-H) and 9.6-
10.4(s, broad, 2H, 2×NH)
disappeared by addition of
D2O
_ 3468 1658 (cyclic and
acyclic amides)
1774-1725
(cyclic imide)
13 _ [M-3]+.
537
3462 1610(α,β-
unsaturated
amide) 1774-
1719 (cyclic
imide)
14 4.42(s, 2H, NCH2), at 6.51 (s,
1H, olefinic proton), at 7.86-
8.0(m, 12H, Ar-H), 9.7-10.5(s,
broad, 2H, 2NH) disappeared
by addition of D2O
_ 3470, 3362 1624(α,β-
unsaturated
amide) 1774-
1718 (cyclic
imide)
15 4.44 (s, 2H, NCH2), 6.94 (s,
1H, olefinic proton), 7.2-
8.7(m, 17H, Ar-H), 9.8-
10.95(s, broad, 2H, 2×NH)
disappeared by addition of
D2O
_ 3360, 3170 1645 (acyclic
amide)
1731 (carbamate
ester)
1774-1740
(cyclic imide)
16 2.49(s, 3H, OCOCH3), at
4.42(s, 2H, NCH2), at 6.76 (s,
1H, olefinic proton), at 7.87-
8.0(m, 12H, Ar-H) and 9.65-
10.5(s, broad, 1H, 1NH)
disappeared by addition of
D2O
_ 3474, 3370 1617(α,β-
unsaturated
amide) 1774-
1718 (cyclic
imide)
17 4.44(s, 2H, NCH2), at 6.74 (s,
1H, olefinic proton), at 7.2-
8.0(m, 12H, Ar-H) and at 9.9-
10.7(s, broad, 1H, NH)
disappeared by addition of
D2O
_ 3470 1618(α,β-
unsaturated
amide) 1774-
1715 (due to
coupling
carbonyl bands of
cyclic imide)
Experimental
121
Compd.No. H1-NMR(δinppm)
MS
(m/z,%)
IR cm-1
νN-H νC=O
18 4.09 (s, 2H, CH2), at 4.42(s,
2H, NCH2), at 5.82 (s, 1H,
olefinic proton), at 7.91-
7.93(m, 16H, Ar-H) and at
9.9-10.7(s, broad, 1H, NH)
disappeared by addition of
D2O
_ 3432 1613(α,β-
unsaturated
amide) 1774-
1721 (cyclic
imides)
19 1.1-2.5 (m, with interference,
5H, COOCH2CH3), at 4.43 (s,
2H, NCH2), at 4.83(s,
2H,OCH2COO), at 6.63(s, 1H,
olefinic proton), at 7.86-7.95
(m, 12H, Ar-H) and 9.5-10.2
(s, broad, 1H, NH)
disappeared by addition of
D2O
_ 3440, 3328 1660 (acyclic
amide)
1774-1719
(cyclic imide)
1731 (ester)
20 4.76 (s, 2H, NCH2), at 4.82(s,
2H, OCH2CO), at 6.72 (s, 1H,
olefinic proton), 7.84-8.1(m,
12H, Ar-H), 9.65-10.5(s,
broad, 2H, 2×NH) disappeared
by addition of D2O
_ 3426 1623(α,β-
unsaturated
amide) 1774-
1719 (cyclic
imide)
21 4.43(s, 2H, NCH2), at 6.51 (s,
1H, olefinic proton), at 7.85-
8.1(m, 12H, Ar-H), 9.65-
10.5(s, broad, 4H, 4×NH)
disappeared by addition of
D2O
_ 3366 1615(α,β-
unsaturated
amide) 1774-
1719 (cyclic
imide)
22 4.6(s, 2H, NCH2), at 6.6 (s,
1H, olefinic proton), at 6.74 (s,
1H, N=CH), at 7.74-8.09(m,
16H, Ar-H) and at 9.6-10.2(s,
broad, 2H, 2×NH) disappeared
by addition of D2O
_ 3424 1615(α,β-
unsaturated
amide) 1774-
1722 (cyclic
imide)
23 4.43(s, 2H, NCH2), at 6.75 (s,
1H, olefinic proton), 7.3-
7.95(m, 12H, Ar-H), at 8.68
(s, broad, 1H, NH) and at
10.69(s, 1H, OH)
_ 3848, 3743,
3485 (OH and
NH)
1617 (cyclic and
a cyclic amide)
1774-1720
(cyclic imide)
24 2.49 (s, 3H, OCOCH3), 4.42(s,
2H, NCH2), at 6.75 (s, 1H,
olefinic proton), 7.87-7.95(m,
12H, Ar-H) and at 9.6-10.2(s,
broad, 1H, NH) disappeared
by addition of D2O
_ 3462, 3328 1660 (cyclic and
acyclic amide)
1774-1720
(cyclic imide)
1731 (ester)
Experimental
121
Compd.No. H1-NMR(δinppm)
MS
(m/z,%)
IR cm-1
νN-H νC=O
25 1.2(t, 3H, CH3), at 4.1(q, 2H,
CH2 of ester), at 4.42 (s, 2H,
NCH2), at 4.83(s,
2H,OCH2COO), at 6.63(s, 1H,
olefinic proton), at 7.4-7.9 (m,
12H, Ar-H) and 9.5-10.2 (s,
broad, 1H, NH) disappeared
by addition of D2O
_ 3440, 3324 1660 (cyclic and
acyclic amide)
1774-1722
(cyclic imide)
1732 (ester)
26 4.42(s, 2H, NCH2), at 4.82(s,
2H, OCH2CO), at 6.6(s, 1H,
olefinic proton), 7.09-8.06(m,
12H, Ar-H), 9.65-10.5(s,
broad, 2H, 2×NH) disappeared
by addition of D2O
_ 3480-3220
(NH and NH2).
1680, 1660
(amides and
hydrazide)
1774-1723
(cyclic imide)
27 4.43(s, 2H, NCH2), at 5.82 (s,
1H, olefinic proton), at 7.85-
8.08 (m, 12H, Ar-H), 9.65-
10.5(s, broad, 4H, 4×NH)
disappeared by addition of
D2O
_ 3462, 3320 1662 (amides)
1774-1718
(cyclic imide)
28 4.43 (s, 2H, NCH2), at 6.5 (s,
1H, olefinic proton), at 6.7 (s,
1H, N=CH), at 7.78-8.09 (m,
16H, Ar-H) and at 9.6-10.2(s,
broad, 2H, 2×NH) disappeared
by addition of D2O
_ 3445 1666 (amides)
1774-1716
(cyclic imide)
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Studies on 4H-3,1-Benzoxazin-4-ones
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123
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ARABIC SUMMERY
Studies on 4H-3,1-Benzoxazin-4-ones
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ذوكلزكسالالالو بوث والالال ز الالالس ( بالالالي ذوكلزكذسل الالالك 2) افبحززازكزاز حالالالستزعالالال زل عذالالالص تفالالال عالالال
زقالالالك نبدالالالث لا الالال (2١)زت ا-٤-كوحالالال ززفوث -ذوكلزكسالالال -ت٣فوعطالالالص خالالال ل افيالالالس سئ ا ب والالالد
( ب عذالالالالد بالالالالي اجروكل الالالالك خةالالالالو اف ذوالالالال خالالالال ل كذسل الالالالك ا والالالال 2١ا تالالالالزات افالالالالك ح بود فذة كالالالال )
.( عذ اف تو 22( ز )22فوعطص افة كب ل )
( ب عذالالالد بالالالي افروالالالكلاز ث 22زات افالالالك ح بود فذة كالالال )بالالالث ج خوالالال نخالالال ش قالالالك نبدالالالث لا الالال ا تالالال
-( بالالالالي ووحوالالالال ا الالالالزز الالالالو ج ل بالالالال لا22( زقالالالالك تالالالالا ت عالالالال افة كالالالال )22ذوالالالالكلال ف عطالالالالص افة كالالالال )
زقالالالالك تالالالالا اخ بالالالال ل افح الالالال .( عذالالالال اف توالالالال 22( ز )22بحزافكذوالالالالك فوعطالالالالص افة كبالالالال ل ) -كذالالالالسلز
.افبوسفس فذة كب ل
143
انهخص انعربي
و تفاعالث بعض انركباث انحهقيت غير يتجاست انحهقت تشييذ
وانتىقع نها شاطا بيىنىجيا( زتفالالال ب عالالال خةالالالو ا ج اجوذالالال 2) ازت -٤-حضالالالو ب الالال ز افبحززازكالالالزاز ثتقالالالكئ ذالالالرخ افكلا الالال ت
ب ف حذالالالال ا بوحالالالال (3a-h)ك ب بس الالال ووحوالالالال ا الالالالو جوذكالب الالالال ق ل (زتحالالالال ١ا كزاززفالالالالست ) ب الالالال زبالالالي
( ب سالالالال وحر بالالالالي افروالالالالكلاز ث ذوالالالالكلال ف عطالالالالص 2) افبحززازكزاز حالالالالست( زتالالالالا والالالال خذقالالالال 2فذة كالالالال )
( بالالالالي اف وحوالالالال ذوالالالالالكلاز ث 2بوحةالالالالال ت عالالالال افة كالالالال ) (4a)ذوكلاز الالالالك خةالالالالو ا ج اجوذالالالال -ب الالالال ز ت
( بأ الالالالالالو س خ ت والالالالالال حالالالالالال 2) افبحززازكزاز حستزبةع فجالالالالالال (4b)ب الالالالالال ز افدوحالالالالالال ززفوحست زنعطالالالالالالص
ع ب افسقت فذ ع .( اع ة ا عذص 2افة ك )
ب الالالال ز ت الالالال ازز ( بالالالالي نز الالالك افيالالالالس سئ فوعطالالالص2) افبحززازكزاز حالالالستبالالالث ج خوالالالال نخالالال ش عالالالال
( تحالالالت فالالال زل و الالالك ك او الالالز بالالالي كالالال بالالالث افبحالالالز ث ز افطسفالالالس ث بعطوالالال 2( ز عالالال افة كالالال )2)
. (7a,b)افدو سج ل افةق بذ
(. 9فالالالال زل بالالالال جق فوعطالالالالص ق عالالالالكل بالالالال جق )( تحالالالالت 2) افبحززازكزاز حالالالالستخالالالال ل تفالالالال عالالالال
(.١1( بعة فوو ل ثح افةو و فوعطص ج ت ذز نفكل )2زكرف ع افة ك )
( بالالالالي ذوكلزكذسل الالالالك افد ب ز الالالالك فوعطالالالالص ب الالالال ز 2) افبحززازكزاز حالالالالستبالالالالث ج خوالالالال نخالالالال ش عالالالال
الالالالال ( ز بيالالالالالر ذالالالالالرا افة كالالالالال عحالالالالالك ل الالالالال خالالالالال الل نعذالالالالال بالالالالالث ل١١اف ا الالالالال زز كوحالالالالال ززفوث )
( بالالالالالالي ثوالالالالالالس افد ب ز الالالالالالك فوعطالالالالالالص 2) افبحززازكزاز حالالالالالالست( ز عالالالالالال ١2اجيالالالالالالر ل عطص افة كالالالالالال )
( .١١افة ك )
( بيالالالالر افة كالالالال ١2)افدوحالالالال ززفوحست -٤-) ب الالالال ز(-٢زعالالالال زل عذالالالالص تفالالالال نبدالالالالث افحيالالالالس عذالالالال
( ب عذالالالالد بالالالالي ع بالالالال 2( بالالالالي خ تالالالال وبسجوسئ زقالالالالك نبدالالالالث لا الالالال ا تالالالالزات افالالالالك ح بود فذة كالالالال )2)
فدذالالال اجروكل الالالك خةالالالو اف ذوالالال ب ذالالالس بالالالث خالالال بي كذسل الالالك اف سالالال سل زاكسالالال كذسل الالالك اف سالالال سل او
) ب الالالالال ز( -٢ -ا الالالالالو و -ت٣ (١2)زتا-٤-كوحالالالالال ززفوث -) ب الالالالال ز(-٢ -) ب الالالالال ز(-٤زت عذة ج الالالالالذوعطص
) -ت٣ (١2)زتا-٤-كوحالالالالالالالالالال ززفوثكذسلز-٤-ووحوالالالالالالالالالال -) ب الالالالالالالالالال ز( -٢ (١2)زتا-٤-كوحالالالالالالالالالال ززفوث -
.( عذ اف تو ١2)زتا-٤-كوح ززفوث -ب ز(
( بالالالي خالالال ل كذسل الالالك ا والالال والالال او الالالو ست افجالالال ل زوالالال ١2بالالالث ج خوالالال نخالالال ش عالالال افة كالالال )
( زقك نبدث لا ا تزات افك ح بود ١9ز س ك بسج ل افبست وسئ افج و فوعطص افة ك )
ت عالالالال افة كالالالال ( زقالالالالك تالالالالا 21( ب عذالالالالد بالالالالي افروالالالالكلاز ث ذوالالالالكلال ف عطالالالالص افة كالالالال )١9فذة كالالالال )
( عذالالالال 22( ز )2١بحزافكذوالالالالك فوعطالالالالص افة كبالالالال ل ) -كذالالالالسلز -( بالالالالي ووحوالالالال ا الالالالزز الالالالو ج ل بالالالال لا21)
.اف تو
قرار لجنة الحكم
سراء عزم عبد الوهابإ اسم الباحث/
تشد و تفاعالت بعض المركبات الحلقة غر متجانسة الحلقة عنوان الرسالة :
والمتوقع لها نشاطا بولوجا
لجنة الحكم والمناقشة
عـــالتوقي ةـــــــالوظيف مــــــــــاالس م
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تاريخ اناقشت:
تقذير انرسانت:
جايعت بها
ىوــــت انعهـــــــكهي
كيياءى انــــــــقس
سراء عزم عبد الوهابإ : اسم الباحث
تشد و تفاعالت بعض المركبات الحلقة غر متجانسة عنوان الرسالة :
والمتوقع لها نشاطا بولوجا الحلقة
هيئة اإلشراف
التوقيـــع الوظيفـــــــة االســــــــــم م
عبد الحمد وصفىأ.د/أشرف 1 –أستاذ الكماء العضوة
قسـم الكمــــاء كلــة العلــوم
بـــــــنهاجامعة
بو العال رضوانأمحمد أ.د/ 2 –ة تطبقأستاذ الكماء ال
الهندسة بشبرا كلــة بـــــــنهاجامعة
.د/عل عبد المعبود عل 3 –الكماء العضوة مساعد أستاذ
الكمــــاءقسـم كلــة العلــوم
بـــــــنهاجامعة
منال محمود طمعت الحفناويد/ 4 –الكماء العضوة مدرس
الهندسة بشبرا كلــةبـــــــنهاجامعة
رئيس يجهس قسى انكيياء
أ.د / شافعى جالل ديا
21١١
جايعت بها
كهيت انعهىو
قسى انكيياء
تشد و تفاعالت بعض المركبات الحلقة غر متجانسة الحلقةوالمتوقع لها نشاطا بولوجا
للحصول على كجزء متمم رسالة مقدمة
درجة الماجستر فى العلوم )كماء عضوة(
مقدمة من سراء عزم عبد الوهابإ
) بكالوريوس علوم قسم الكيمياء(
مقدمه الى
جامعة بنها –كلة العلوم –قسم الكماء
تحت إشراف
أ.د/أشرف عبد الحمد فاروق وصفى العضوة الكماء أستاذ
قسـم الكمــــاء كلـة العلــوم
ـنهابجامعة
بو العال رضوانأمحمد أ.د/ التطبقة الكماء أستاذ
الهندسة بشبرا كلـة نهاجامعة بـ
عل عل عبد المعبودد/ الكماء العضوة مساعد أستاذ
الكمــــاء قسـم العلوم كلـة
بنها جامعة
منال محمود طلعت الحفناويد/ مدرس الكماءالعضوة
كلـة الهندسة بشبرا نهاجامعة بـ